All the three trials reported 3-year OS, and all the trials claimed that there was no statistical difference between experimental and control groups, which is consistent with our traditional and cumulative meta-analysis (HR for 3-year OS was 0.78, 95% CI: 0.57–1.06, P=0.90; Figure 3B). No publication bias was detected (Egger’s regression intercept P-value =0.9047>0.05, Figure S4), and the pooled HRs for consolidation and maintenance therapy studies were 0.81 (95% CI: 0.53–1.25) and 0.75 (95% CI: 0.48–1.16), respectively.
Meta-analysis of the available data from all the three trials suggested that the frequencies of both overall adverse event (AE) and grades 3 and 4 peripheral neuropathy (PN) were similar in the bortezomib-based groups and the non-bortezomib-based groups (P=0.12 and P=0.41, respectively). Cumulative meta-analysis indicated that there were similar frequencies of grades 3 and 4 PN between bortezomib-based and non-bortezomib-based groups when maintenance treatment was added to the meta-analysis (OR =1.62, 95% CI: 0.73–3.61) (Figure 4), while there was a significant difference between bortezomib-based groups and non-bortezomib-based groups when the cumulative meta-analysis just included the consolidation treatment (OR =4.26, 95% CI: 1.06–17.11). No publication bias was detected (Egger’s regression intercept P-value was 0.619>0.05, Figure S5), and the pooled ORs for consolidation and maintenance therapy studies were 4.26 (95% CI: 1.06–17.11) and 0.73 (95% CI: 0.24–2.27), respectively. Meanwhile, both neutropenia and thrombocytopenia were more frequently observed in bortezomib-based group after ASCT (data not fully shown).
(To view a larger version of Figure 4, click here.)
Although HDT followed by ASCT (HDT–ASCT) has been established as the frontline therapy for young patients with newly diagnosed MM, post-transplantation treatment aimed at enhancing the rate and quality of response achieved in the previous treatment phase (consolidation), and reducing the risk of progression or relapse and to prolong survival period (maintenance) is necessary.23,24 To evaluate the efficacy and safety of bortezomib-based regimen administered as consolidation or maintenance therapy after ASCT, we conducted this meta-analysis of three RCTs.11–13
In our integrated analyses, the rate of CR/nCR (53.0% vs 39.8%) after transplantation was higher in bortezomib-based therapy groups than that in non-bortezomib-based therapy groups, indicating consistent conclusion with previous meta-analysis performed by Sonneveld et al which demonstrated that in the bortezomib-based induction groups, the CR/nCR rate after transplantation was significantly higher compared with that in the non-bortezomib-based induction groups (38% vs 24%, OR =2.05, 95% CI: 1.64–2.56).25 Interestingly, an obvious difference between these two analyses was found, showing that the CR/nCR rates, both in bortezomib-based and non-bortezomib-based therapy groups, were significantly higher after post-transplantation therapy compared with those observed after ASCT. High-quality CR/nCR rates were observed more frequently and obtained more rapidly in previous studies in which bortezomib was incorporated into a multiagent combination regimen for both induction prior to and consolidation after tandem transplant. Hence, we can draw a conclusion that post-transplantation therapy with the goal to enhance the rate and quality of response obtained in the previous treatment phase(s) is well worth applying; Meanwhile, because a total number of 573 (37.7%) participants in the bortezomib-based groups had a history of bortezomib exposure in two RCTs, which might have contributed to the higher CR/nCR rate, we can speculate that the administration of bortezomib into induction, consolidation, and maintenance regimen is worth application in MM treatment. Furthermore, our cumulative meta-analysis confirmed a superiority in CR/nCR and ORR rates when bortezomib-based regimen was administered as a maintenance therapy rather than consolidation therapy ([OR =1.86, 95% CI: 1.40–2.46 vs OR =1.62, 95% CI: 1.18–2.22] and [OR =1.93, 95% CI: 1.28–2.92 vs OR =1.63, 95% CI: 0.81–3.28], respectively), and the difference between consolidation therapy and maintenance therapy could be attributed to an accumulative effect of bortezomib during the longer period of treatment. Based on these results, we conclude that maintenance therapy with bortezomib-containing regimen is worth consideration in order to get higher response rate.
Our integrated analysis suggested that bortezomib-based post-transplantation treatment improved PFS with a pooled HR 0.73 with low heterogeneity (I2 =0%), and our cumulative meta-analysis indicated that both consolidation and maintenance therapy could improve PFS. The benefit of bortezomib-based treatment after ASCT has already been established by several other studies; however, the overall effect of HR demonstrated in our integrated analysis could be introduced as a reference for further investigation of the extent of PFS improvement in future studies. Meanwhile, as stated earlier, no significant difference can be found in OS between bortezomib-based and non-bortezomib-based groups (P=0.90). Relatively short follow-up time, highly effective salvage therapy after disease progression, and a median OS estimate of 7–8 years in young newly diagnosed MM patients eligible for transplantation might have contributed to the similarity in OS between experimental and control groups. Additionally, in a Phase III trial of lenalidomide plus dexamethasone, an improved OS was observed during prolonged follow-up.26 Thus, an evident OS benefit might be confirmed in long-term follow-up.