Bortezomib Induction and Maintenance in Patients with Newly Diagnosed Multiple Myeloma: Long-Term Follow-Up of the HOVON-65/GMMG-HD4 Trial

For transplant-eligible patients with multiple myeloma (MM), high-dose melphalan (HDM) followed by autologous stem-cell transplantation (ASCT) is regarded as the standard of care. The HOVON-65/GMMG-HD4 trial had previously demonstrated that incorporation of bortezomib to induction and maintenance regimens followed by HDM and ASCT resulted in a significant improvement in progression-free survival (PFS) and overall survival (OS) in transplant-eligible patients with newly diagnosed MM compared with standard regimens; Sonneveld and colleagues reported the long-term follow-up results of this trial at ASH 2015.^1,2

In the trial, 827 eligible patients were randomized to receive standard induction therapy with vincristine/doxorubicin/dexamethasone (VAD) or the bortezomib-containing regimen of bortezomib/doxorubicin/dexamethasone (PAD). Following HDM/ASCT, maintenance therapy consisted of a daily thalidomide (T) regimen in the VAD arm or 2 weekly bortezomib (B) treatments in the PAD arm for 2 years. After a median follow-up of 91.4 months, response rates were significantly higher in the bortezomib-containing arm (PAD/HDM/B) compared with the standard arm (VAD/HDM/T), in terms of complete response (37% vs 25%), ?very good partial response (VGPR; 76% vs 56%), and ?partial response (PR; 91% vs 83%). PFS was significantly higher in the bortezomib-containing arm (PFS at 96 months: 17% vs 10%; hazard ratio, 0.77; P = .001) compared with the standard arm. While this did not translate to an OS benefit in the primary analysis, restricted mean survival time at 8 years showed prolonged survival by 4.8 months with bortezomib therapy (P = .04). In the bortezomib-containing arm, administration of single versus double HDM/ASCT did not impact PFS at 96 months; however, OS at 96 months was improved with double HDM/ASCT (42% vs 55%). The findings of a subgroup analysis in 395 patients who underwent double HDM/ASCT based on presence or absence of adverse chromosomal abnormalities showed 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 gain (1q) abnormalities. Similar improvements in PFS at 96 months and OS at 96 months were achieved with PAD therapy by high-risk patients presenting with elevated creatinine >2 mg/dL. The long-term results of the HOVON-65/GMMG-HD4 trial showed that bortezomib-based induction and maintenance leads to significant and durable survival improvements, and significantly reduces the unfavorable effects of del(17p) and renal impairment on survival.

1. Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955.
2. Sonneveld P, et al. ASH 2015. Abstract 27.