Cyclosporin A combined with vincristine, doxorubicin and dexamethasone (VAD) compared with VAD alone in patients with advanced refractory multiple myeloma: an EORTC-HOVON randomized phase III study (06914).
Patients with multiple myeloma (MM) refractory to alkylating agents frequently express P-glycoprotein (Pgp), which is associated with the multidrug resistance (MDR) phenotype. We have conducted a randomized phase II/III study of the MDR reversal agent cyclosporin A combined with VAD (vincristine, doxorubicin, dexamethasone) compared with standard VAD in patients with MM stage IIA/IIIA who were refractory to or progressive after treatment with alkylating agents. Out of 81 patients who were randomized, 75 were eligible and evaluable: 34 in the VAD + cyclosporin A arm versus 41 in the VAD arm. Toxicities of grade 2-3 were observed more often with VAD + cyclosporin A than with VAD only: nausea (30% versus 8%, P = 0.015), mucositis (18% versus 5%, P = 0.13), infection (45% versus 35%, P = 0.50). The treatment results were similar in the two arms: 53% versus 49% responded [95% CI (-18.5%, 26.9%)]. The median progression-free survival (PFS) was 8.6 months (VAD + cyclosporin A) versus 5.8 months (VAD): [log rank P = 0.16, hazard ratio = 0.71, 95% CI (0.44, 1.15)], and median overall survival was 13 months versus 14.6 months [log rank P = 0.89, hazard ratio = 0.96, 95% CI (0.62, 1.72)]. The cause of death was progressive disease (85%), toxicity (10%) or other (5%). Bone marrow analysis performed in 23 patients showed that the response rate was 67% in Pgp-positive versus 55% in Pgp-negative patients. Cyclosporin A combined with VAD is relatively well tolerated. There is no effect of cyclosporin A on the overall response rate, PFS and overall survival with VAD.
Sonneveld
P
P
Department of Haematology, University Hospital Rotterdam Dijkzigt, Room L407, 3000 CA Rotterdam, TheNetherlands. sonneveld@hema.fgg.eur.nl
Suciu
S
S
Weijermans
P
P
Beksac
M
M
Neuwirtova
R
R
Solbu
G
G
Lokhorst
H
H
van der Lelie
J
J
Dohner
H
H
Gerhartz
H
H
Segeren
C M
CM
Willemze
R
R
Lowenberg
B
B
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016009:Chi-Square Distribution; D016572:Cyclosporine / Q000008:administration & dosage*; D003907:Dexamethasone / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D018432:Drug Resistance, Multiple; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D016016:Proportional Hazards Models; D011446:Prospective Studies; D015996:Survival Rate; D014750:Vincristine / Q000008:administration & dosage
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014750:Vincristine; D003907:Dexamethasone; D004317:Doxorubicin; D016572:Cyclosporine