Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial

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) 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.

Frontline treatment for transplant‐eligible multiple myeloma: A 6474 patients network meta‐analysis

“…We have arbitrarily allocated similar multidrug protocols based on their drug profile, resulting in 11 individual treatment groups: TT2- 35,38,43,45 (Bortezomib, Doxorubicin, and Dexamethasone), CRD (Cyclophosphamide, Lenalidomide, and Dexamethasone), 11,12 and Dex 44 (High Dose Dexamethasone). Network plots for all outcomes are presented in Figure 2.…”

Ixazomib maintenance therapy in newly diagnosed multiple myeloma: An integrated analysis of four phase I/II studies

“…There is increasing evidence for the clinical benefit of long-term, continuous therapy in patients with newly diagnosed multiple myeloma (NDMM), irrespective of whether they undergo autologous stem cell transplantation (ASCT). [1][2][3][4][5][6][7][8] Studies suggest that patients with NDMM who receive continuous treatment until first disease progression have prolong ed progression-free (PFS) and overall (OS) survival vs those who receive fixed-duration therapy, 1,8,9 although across studies the OS b enefits associated with prolonged treatment were not consistent a nd may have been less pronounced than the observed PFS improvem ents. 1,6,10 Lenalidomide is the only agent currently approved in the United States and EU for use as maintenance therapy; however, it is only approved following ASCT in patients with NDMM.…”

“…11,12 Proteasome inhibitors (PIs) are a cornerstone of therapy for many patient s with multiple myeloma (MM). 13,14 Maintenance with bortezomib has been extensively studied and has demonstrated PFS improvements 2,7 ; however, long-term treatment with bortezomib may be limit ed due to toxicity and the need for regular parenteral administration, which can increase treatment burden. 7,[15][16][17][18][19] Ixazomib is the first oral PI to be approved for MM, for use in combination with lenalidomide-dexamethasone (Rd) in patients with MM who have received ≥ 1 p rior therapy.…”

Cytogenetic aberrations in multiple myeloma are associated with shifts in serum immunoglobulin isotypes distribution and levels

“…9,10 For purpose of replication, an independent cohort of 325 cases from GMMG-HD4 trial was obtained. 11,12 Blood samples were collected prior to treatment initiation in the above trials, coordinated by University Clinic Heidelberg. Patient characteristics are summarized in Online Supplementary Table S1; see details.…”