Phase I trial of first-line bortezomib/thalidomide plus chemotherapy for induction and stem cell mobilization in patients with multiple myeloma.
BACKGROUND
In preclinical studies, bortezomib was shown to suppress tumor growth, sensitize malignant cells to apoptosis, and reverse chemotherapy resistance.


METHODS
We evaluated the addition of escalating doses of bortezomib 0.7, 1, and 1.3 mg/m2 intravenously on days 1, 4, and 8 to DT-PACE (cisplatin 10 mg/m2, doxorubicin 10 mg/m2, cyclophosphamide 400 mg/m2, and etoposide 40 mg/m2 per day by intravenous continuous infusion on days 1-4) plus oral dexamethasone 40 mg on days 1-4 and thalidomide 200 mg on days 1-8 in newly diagnosed patients with multiple myeloma. Peripheral blood stem cells were collected after cycle 1. Twelve patients completed the study, and all received autologous stem cell transplantation (SCT).


RESULTS
Hematologic toxicities were predictable, with 3 episodes of neutropenic fever. Grade >/= 2 nonhematologic toxicities included diarrhea (n = 1), deep vein thrombosis (n = 2), hypotension (n = 2), syncope (n = 1), and peripheral neuropathy (n = 3). The median number of CD34+ cells collected was 20.57 x 10 superset6 CD34+ cells/kg. After 2 cycles, 10 of 12 patients exhibited a partial response or better. Best response after autologous SCT, complete response/near complete response was exhibited in 9 patients, and partial response was exhibited in 3 patients. At a median of 20 months, 4 patients experienced relapse and 1 had died. Bortezomib/DT-PACE compared favorably with DT-PACE with regard to leukapheresis days, total CD34+ cell collection, and engraftment.


CONCLUSIONS
This novel strategy of simultaneous proteasome inhibition in combination with thalidomide and chemotherapy was effective and safe, allowing for adequate stem cell collection and early autologous SCT; its impact on overall survival, especially in patients with high-risk myeloma, awaits further investigation.
Badros
Ashraf
A
University of Maryland Greenebaum Cancer Center, Baltimore, MD, USA. abadros@umm.edu
Goloubeva
Olga
O
Fenton
Robert
R
Rapoport
Aaron P
AP
Akpek
Gorgun
G
Harris
Carolynn
C
Ruehle
Kathleen
K
Westphal
Sandra
S
Meisenberg
Barry
B
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage*; D000069286:Bortezomib; D002945:Cisplatin / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000627:therapeutic use; D003907:Dexamethasone / Q000008:administration & dosage / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000627:therapeutic use; D005047:Etoposide / Q000627:therapeutic use; D005260:Female; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000628:therapy*; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage*; D012074:Remission Induction; D033581:Stem Cell Transplantation; D013792:Thalidomide / Q000008:administration & dosage* / Q000627:therapeutic use; D016896:Treatment Outcome
D001897:Boronic Acids; D061988:Proteasome Inhibitors; D011719:Pyrazines; D013792:Thalidomide; D000069286:Bortezomib; D005047:Etoposide; D003907:Dexamethasone; D004317:Doxorubicin; D003520:Cyclophosphamide; D002945:Cisplatin