High-dose melphalan (HDM) followed by autologous stem-cell transplantation (ASCT) is the standard of care for transplant-eligible patients with multiple myeloma (MM). Sonneveld and colleagues reported the long-term follow-up results of the HOVON-65/GMMG-HD4 trial, which had previously demonstrated bortezomib-based induction and maintenance regimens followed by HDM and ASCT significantly improved survival outcomes in transplant-eligible patients with newly diagnosed MM compared with standard.1,2 The HOVON-65/GMMG-HD4 trial randomized 827 eligible patients to standard induction therapy with vincristine/doxorubicin/dexamethasone or the bortezomib-based bortezomib/doxorubicin/dexamethasone regimen, followed by HDM/ASCT. Patients received maintenance therapy with a daily thalidomide regimen (control) or twice-weekly bortezomib treatment in the experimental arm for 2 years.
At a median follow-up of 91.4 months, patients who received bortezomib-based regimen achieved significantly higher rates of complete response (37% vs 25%), ≥very good partial response (26% vs 21%), and overall response rate (91% vs 83%) compared with the standard regimen. Median progression-free survival (PFS) was significantly prolonged with bortezomib-based regimen (34 months vs 28 months; hazard ratio, 0.77; P = .001) compared with standard regimen. However, this PFS benefit did not translate into an improvement in overall survival (OS; median OS: 90 months vs 83 months) in the primary analysis, although a significant prolongation by 4.8 months was observed in a univariate analysis (P = .04). The bortezomib-containing cohort derived a significant OS benefit at 60 months with double HDM/ASCT (71% vs 60%; P = .04), whereas administration of single versus double HDM/ASCT did not provide PFS benefit at 60 months. Subgroup analysis (n = 395) based on presence or absence of adverse chromosomal abnormalities found that bortezomib treatment plus double HDM/ASCT in the subset of patients with del(17p) significantly improved PFS and OS, while it did not benefit patients with t(4;14) and add(1q) abnormalities. Patients with renal impairment (serum creatinine >2 mg/dL) also achieved similar improvements in PFS at 60 months (32% vs 5%; P = .001) and OS at 60 months (66% vs 21%; P <.001). Based on these results, the authors concluded that bortezomib-based induction and maintenance was associated with significant and durable survival improvements, and may significantly reduce the unfavorable effects of del(17p) and renal impairment on survival of patients with newly diagnosed MM.
- Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955.
- Sonneveld P, et al. ASH 2015. Abstract 27