Objective: To evaluate the efficacy and safety of bortezomib-based vs non-bortezomib-based post-transplantation therapy in patients with multiple myeloma.
Methods: Data of relevant randomized controlled trials assessing the effect of bortezomib as post-transplantation consolidation or maintenance therapy was obtained through a comprehensive search. The outcome measures included response rate, progression-free survival, overall survival, and adverse events (AEs). The hazard ratio (HR), Cochran-Mantel-Haenszel odds ratio (OR), and 95% confidence interval (95% CI) were applied to evaluate the effect of bortezomib in relation to the end points such as progression-free survival, overall survival, response rate, and AEs.
Results: Three randomized controlled trials comprising 1,518 participants were included in this study. Pooled ORs for the rates of overall response, and complete response and near complete response, were 1.85 and 1.75, respectively. Pooled HR for progression-free survival favored bortezomib-based therapy over non-bortezomib-based therapy (0.73, 95% CI: 0.67–0.81), while no statistically significant difference could be found between the two groups regarding the pooled HR for 3-year overall survival. Moreover, incidence rates of overall adverse events and grade 3 and 4 peripheral neuropathy were similar in the bortezomib-based groups and the non-bortezomib-based groups (P=0.12 and P=0.41, respectively). The corresponding cumulative meta-analyses of the rates of overall response rate, complete response and near complete response, and grades 3 and 4 peripheral neuropathy supported the superiority of bortezomib-based maintenance therapy over consolidation therapy.
Conclusion: Bortezomib-based therapy after autologous stem cell transplantation, with tolerable AEs, could obviously improve the response as well as the outcome of multiple myeloma patients, particularly when bortezomib was administered as maintenance therapy.
Keywords: multiple myeloma, post-transplantation therapy, bortezomib-based regimen
Multiple myeloma (MM), a common hematological malignancy originates from defects in plasma cells and accounts for 20% of all deaths caused by hematological malignancies.1 Although the clinical application of high-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) significantly improves the survival rate in newly diagnosed MM, the clinical relapse after a certain period of remission is still inevitable in most patients.2 Therefore, post-transplantation therapy such as consolidation (2–4 cycles of combination therapies) and/or maintenance (continuous therapy, usually with single agents, until disease progression) is considered as a promising strategy for achieving durable remission and preventing tumor progression.
Several randomized controlled trials (RCTs) have evaluated the outcome of post-transplantation therapy. Administration of interferon-α was associated with marginally beneficial effects on progression-free survival (PFS) and overall survival (OS). However, due to toxic side effects and poor tolerance, interferon-α maintenance therapy after transplantation is rarely used nowadays.3 Although maintenance therapy with corticosteroid has prolonged PFS, its effect on OS remains controversial.4,5Immunomodulatory drugs such as thalidomide and lenalidomide, which have been studied as maintenance therapy during the post-transplantation period, have shown improvements, particularly in terms of PFS, while their effects on OS are still debatable.6–8 In addition, a recent study demonstrated that maintenance therapy with lenalidomide could impair the thymic T-cell reconstitution, probably jeopardizing the immunological surveillance over a long period of follow-up.9
Bortezomib is a selective and reversible proteasome inhibitor, which is associated with a high response rate observed both in newly diagnosed MM patients and patients with relapsed or refractory MM.10 It has been used in the consolidation or maintenance therapy for patients who have previously undergone ASCT in several RCTs,11–13 where bortezomib-based therapy after ASCT was compared with non-bortezomib-based therapy; these included trials NCT001134484, NCT00417911, and HOVON-65/GMMG-HD4, in which bortezomib-thalidomide-dexamethasone was compared with thalidomide-dexamethasone (VTD vs TD); bortezomib with placebo; and bortezomib-doxorubicin-dexamethasone with vincristine-doxorubicin-dexamethasone (VAD), respectively. Each study met its primary objective, in which significant improvements in response rates as well as substantial improvements in PFS/time to progression (TTP) were consistently demonstrated, favoring bortezomib-based against non-bortezomib-based post-transplantation therapy. Therefore, we conducted a meta-analysis of data from these Phase III studies to characterize the overall effect of bortezomib-based vs non-bortezomib-based post-transplantation therapy. Complete response (CR) and/or near complete response (nCR) rate, PFS, and OS were the three key end points during post-transplantation treatments.