Long-term results of the HOVON-65/GMMG-HD4 trial: bortezomib before and after high-dose therapy

The use of bortezomib as frontline high-dose therapy for Multiple Myeloma (MM) patients receiving high-dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT), has been established by the Dutch-Belgian Cooperative Trial Group for Hematology and Oncology Group-65/German-speaking Myeloma Multicenter Group HD4 (HOVON-65/GMMG-HD4). In order for a better assessment of maintenance and overall survival (OS) from this first line treatment, as well as the chance to detect secondary primary malignancies (SPMs), a long-term follow-up of this study  was carried out. The results of the phase III investigator-sponsored, open-label, multicenter trial were published in Leukemia, in August 2017.

Key findings

• Patients (pts) involved in the trial = 827; age = 18-65 years
• Pts received either VAD (vincristine, doxorubicin, dexamethasone) induction followed by HDM and thalidomide maintenance, or PAD (bortezomib, doxorubicin, dexamethasone) HDM and bortezomib maintenance
• Median follow-up = 96 months
• Median Progression Free Survival (PFS): VAD arm = 29 months (95% CI: 25–32) vs PAD arm = 34 months (95% CI: 30–38); PAD arm vs VAD arm: HR = 0.79 (95% CI 0.68–0.92); P = 0.003
• Median PFSa (PFS calculated without censoring at time of alloSCT): VAD arm = 29 months (95% CI: 25–32) vs PAD arm = 34 months (95% CI: 30–38)
• Median Overall Survival (OS): VAD arm = 82 months (95% CI: 67–96) vs PAD arm = 91 months, (95% CI: 83–108)
• 3-year OS: 72% (95% CI: 67–76%) vs 79% (95% CI: 74–82%) and 5-year OS: 59% (95% CI: 54–64%) vs 65% (95% CI: 60–70%) in VAD vs PAD arm
• Long-term OS at 96 months: VAD arm = 45% (95% CI: 40–50%) vs PAD arm = 48% (95% CI: 43–53%); HR = 0.89, (95% CI: 0.74—1.08) P = 0.24
• Median OS from first progressive disease/relapse: VAD 40 months (95% CI: 34–-47 months) vs PAD 43 months (95% CI: 35–48 months)
• Data via cytogenetic abnormalities:
  • 17p13 deletion: PFS for PAD arm P = 0.48 vs VAD arm P = <0.001; OS for PAD arm P = 0.54 vs VAD arm P = <0.001; OS rates at 96 months = 52% VAD vs 54% PAD, p = 0.54
  • t(4;14) translocation and 1q21 gain: no significant differences
• Data via renal impairment:
  • VAD treatment had no long-term impact on PFS: PAD arm (P = 0.56) vs VAD arm (P = <0.001), OS: PAD arm (P = 0.74) vs VAD arm (P = 0.001)
  • OS at 96 months (with vs without renal impairment): VAD = 12% with vs 49%; PAD = 47% vs 48%
• SPM incidence for both VAD and PAD arms = 7%, P = 0.73

Conclusion

This long-term follow-up confirmed the finding that bortezomib prolongs PFS, but did not provide a statistically significant OS compared with classical cytotoxic agents. However, bortezomib was not associated with increased emergence of SPM, and bortezomib induction and maintenance therapy showed sustained improvement in both PFS and PFSa compared with classical cytotoxic agents in combination with thalidomide. Additionally, PFS was significantly better in the PAD treatment arm compared with the VAD treatment arm. The negative prognosis for patients with the 17p13 deletion and renal impairment were abrogated in the PAD arm, but not in the VAD treatment arm. The authors concluded that using bortezomib with HDM remains a good standard of care for MM patients eligible for transplantation.

Abstract

The Dutch-Belgian Cooperative Trial Group for Hematology Oncology Group-65/German-speaking Myeloma Multicenter Group-HD4 (HOVON-65/GMMG-HD4) phase III trial compared bortezomib (BTZ) before and after high-dose melphalan and autologous stem cell transplantation (HDM, PAD arm) compared with classical cytotoxic agents prior and thalidomide after HDM (VAD arm) in multiple myeloma (MM) patients aged 18-65 years. Here, the long-term follow-up and data on second primary malignancies (SPM) are presented. After a median follow-up of 96 months, progression-free survival (censored at allogeneic transplantation, PFS) remained significantly prolonged in the PAD versus VAD arm (hazard ratio (HR)=0.76, 95% confidence interval (95% CI) of 0.65-0.89, P=0.001). Overall survival (OS) was similar in the PAD versus VAD arm (HR=0.89, 95% CI: 0.74-1.08, P=0.24). The incidence of SPM were similar between the two arms (7% each, P=0.73). The negative prognostic effects of the cytogenetic aberration deletion 17p13 (clone size ⩾10%) and renal impairment at baseline (serum creatinine >2 mg dl^-1) on PFS and OS remained abrogated in the PAD but not VAD arm. OS from first relapse/progression was similar between the study arms (HR=1.02, P=0.85). In conclusion, the survival benefit with BTZ induction/maintenance compared with classical cytotoxic agents and thalidomide maintenance is maintained without an increased risk of SPM.Leukemia advance online publication, 1 August 2017; doi:10.1038/leu.2017.211.