Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression.
OBJECTIVE
This phase III international study compared the efficacy and safety of a combination of pegylated liposomal doxorubicin (PLD) plus bortezomib with bortezomib monotherapy in patients with relapsed or refractory multiple myeloma.


METHODS
Six hundred forty-six patients were randomly assigned to receive either intravenous bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11 of an every 21-days cycle, or the same bortezomib regimen with PLD 30 mg/m(2) on day 4.


RESULTS
Median time to progression was increased from 6.5 months for bortezomib to 9.3 months with the PLD + bortezomib combination (P = .000004; hazard ratio, 1.82 [monotherapy v combination therapy]; 95% CI, 1.41 to 2.35). The 15-month survival rate for PLD + bortezomib was 76% compared with 65% for bortezomib alone (P = .03). The complete plus partial response rate was 41% for bortezomib and 44% for PLD + bortezomib, a difference that was not statistically significant. Median duration of response was increased from 7.0 to 10.2 months (P = .0008) with PLD + bortezomib. Grade 3/4 adverse events were more frequent in the combination group (80% v 64%), with safety profiles consistent with the known toxicities of the two agents. An increased incidence in the combination group was seen of grade 3/4 neutropenia, thrombocytopenia, asthenia, fatigue, diarrhea, and hand-foot syndrome.


CONCLUSIONS
PLD with bortezomib is superior to bortezomib monotherapy for the treatment of patients with relapsed or refractory multiple myeloma. The combination therapy is associated with a higher incidence of grade 3/4 myelosuppression, constitutional symptoms, and GI and dermatologic toxicities.
Orlowski
Robert Z
RZ
Department of Medicine, Division of Hematology/Oncology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA. R_Orlowski@med.unc.edu
Nagler
Arnon
A
Sonneveld
Pieter
P
Bladé
Joan
J
Hajek
Roman
R
Spencer
Andrew
A
San Miguel
Jesús
J
Robak
Tadeusz
T
Dmoszynska
Anna
A
Horvath
Noemi
N
Spicka
Ivan
I
Sutherland
Heather J
HJ
Suvorov
Alexander N
AN
Zhuang
Sen H
SH
Parekh
Trilok
T
Xiu
Liang
L
Yuan
Zhilong
Z
Rackoff
Wayne
W
Harousseau
Jean-Luc
JL
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage*; D000069286:Bortezomib; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000453:epidemiology; D018450:Disease Progression; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy*; D009364:Neoplasm Recurrence, Local; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D011719:Pyrazines / Q000008:administration & dosage*
D001897:Boronic Acids; D011719:Pyrazines; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D000069286:Bortezomib; D004317:Doxorubicin