A phase III randomized study of oral verapamil as a chemosensitizer to reverse drug resistance in patients with refractory myeloma. A Southwest Oncology Group study.
BACKGROUND
Multiple myeloma is considered to be a drug responsive disease; however, there is no cure for this disease and virtually all patients will develop drug resistance. One form of drug resistance that has been documented is the multidrug resistance phenotype or MDR.


METHODS
A randomized trial of the combination of vincristine, doxorubicin, and dexamethasone (VAD) and VAD plus oral verapamil (VAD/v) in drug refractory multiple myeloma patients was performed by the Southwestern Oncology Group. Verapamil was used as a chemosensitizing agent to attempt to overcome or prevent MDR and improve the therapeutic outcome.


RESULTS
Response rates between the two treatment arms were similar with an overall response rate of 41% for the VAD alone arm and 36% for the VAD/v arm. Overall survival of patients was also similar with a median survival of 10 months for the VAD arm and 13 months for the VAD/v arm. The toxicity profile was also similar for both treatments, with myelosuppression being the dose-limiting toxicity. No significant correlation was observed between expression of P-glycoprotein, serum verapamil levels, and response to therapy.


CONCLUSIONS
No beneficial effect was observed from the addition of oral verapamil to the VAD chemotherapy regimen for the treatment of drug-resistant myeloma patients. More effective and less toxic chemosensitizers are needed to study the role of chemosensitizers in reversing MDR in the clinic.
Dalton
W S
WS
University of Arizona Cancer Center, Tucson.
Crowley
J J
JJ
Salmon
S S
SS
Grogan
T M
TM
Laufman
L R
LR
Weiss
G R
GR
Bonnet
J D
JD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003907:Dexamethasone / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D018432:Drug Resistance, Multiple; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D012074:Remission Induction; D015996:Survival Rate; D014481:United States; D014700:Verapamil / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D014750:Vincristine / Q000008:administration & dosage
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D014750:Vincristine; D003907:Dexamethasone; D004317:Doxorubicin; D014700:Verapamil