Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial.
OBJECTIVE
We investigated whether bortezomib during induction and maintenance improves survival in newly diagnosed multiple myeloma (MM).


METHODS
In all, 827 eligible patients with newly diagnosed symptomatic MM were randomly assigned to receive induction therapy with vincristine, doxorubicin, and dexamethasone (VAD) or bortezomib, doxorubicin, and dexamethasone (PAD) followed by high-dose melphalan and autologous stem-cell transplantation. Maintenance consisted of thalidomide 50 mg (VAD) once per day or bortezomib 1.3 mg/m(2) (PAD) once every 2 weeks for 2 years. The primary analysis was progression-free survival (PFS) adjusted for International Staging System (ISS) stage.


RESULTS
Complete response (CR), including near CR, was superior after PAD induction (15% v 31%; P < .001) and bortezomib maintenance (34% v 49%; P < .001). After a median follow-up of 41 months, PFS was superior in the PAD arm (median of 28 months v 35 months; hazard ratio [HR], 0.75; 95% CI, 0.62 to 0.90; P = .002). In multivariate analysis, overall survival (OS) was better in the PAD arm (HR, 0.77; 95% CI, 0.60 to 1.00; P = .049). In high-risk patients presenting with increased creatinine more than 2 mg/dL, bortezomib significantly improved PFS from a median of 13 months to 30 months (HR, 0.45; 95% CI, 0.26 to 0.78; P = .004) and OS from a median of 21 months to 54 months (HR, 0.33; 95% CI, 0.16 to 0.65; P < .001). A benefit was also observed in patients with deletion 17p13 (median PFS, 12 v 22 months; HR, 0.47; 95% CI, 0.26 to 0.86; P = .01; median OS, 24 months v not reached at 54 months; HR, 0.36; 95% CI, 0.18 to 0.74; P = .003).


CONCLUSIONS
Bortezomib during induction and maintenance improves CR and achieves superior PFS and OS.
Erasmus Medical Center, Rotterdam, the Netherlands. p.sonneveld@erasmusmc.nl
Pieter
P
Sonneveld
Ingo G H
IG
Schmidt-Wolf
Bronno
B
van der Holt
Laila
L
El Jarari
Uta
U
Bertsch
Hans
H
Salwender
Sonja
S
Zweegman
Edo
E
Vellenga
Annemiek
A
Broyl
Igor W
IW
Blau
Katja C
KC
Weisel
Shulamiet
S
Wittebol
Gerard M J
GM
Bos
Marian
M
Stevens-Kroef
Christof
C
Scheid
Michael
M
Pfreundschuh
Dirk
D
Hose
Anna
A
Jauch
Helgi
H
van der Velde
Reinier
R
Raymakers
Martijn R
MR
Schaafsma
Marie-Jose
MJ
Kersten
Marinus
M
van Marwijk-Kooy
Ulrich
U
Duehrsen
Walter
W
Lindemann
Pierre W
PW
Wijermans
Henk M
HM
Lokhorst
Hartmut M
HM
Goldschmidt
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001897:Boronic Acids / Q000008:administration & dosage*; D000069286:Bortezomib; D003907:Dexamethasone / Q000008:administration & dosage / Q000627:therapeutic use; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy*; D011719:Pyrazines / Q000008:administration & dosage*; D012074:Remission Induction; D013792:Thalidomide / Q000008:administration & dosage; D014750:Vincristine / Q000627:therapeutic use
D001897:Boronic Acids; D011719:Pyrazines; D013792:Thalidomide; D014750:Vincristine; D000069286:Bortezomib; D003907:Dexamethasone; D004317:Doxorubicin