Phase II study of G3139, a Bcl-2 antisense oligonucleotide, in combination with dexamethasone and thalidomide in relapsed multiple myeloma patients.
OBJECTIVE
Bcl-2 regulates the mitochondrial apoptosis pathway that promotes chemotherapy resistance. Bcl-2 antisense oligonucleotide, G3139, targets Bcl-2 mRNA.


METHODS
G3139 was administered (3 to 7 mg/kg/d for 7 days) by continuous intravenous infusion. On day 4, patients started thalidomide (100 to 400 mg as tolerated) and dexamethasone (40 mg daily for 4 days) on 21-day cycles for three cycles. Stable and responding patients continued on 35-day cycles for 2 years.


RESULTS
Thirty-three patients (median age, 60 years; range, 28 to 76 years) received 220 cycles. Patients received a median of three prior regimens including thalidomide (n = 15) and stem-cell transplantation (n = 31). The regimen was well tolerated; the median number of cycles per patient was eight (range, one to 16+ cycles). Toxicities included reversible increase in creatinine, thrombocytopenia, neutropenia, fatigue, anorexia, constipation, fever, neuropathy, edema, electrolyte disturbances, and hyperglycemia. Fifty-five percent of patients had objective responses, including two complete responses (CRs), four near CRs (positive immunofixation), and 12 partial responses; six patients had minimal responses (MRs). Of patients who received prior thalidomide, seven had objective responses, and three had MRs. The median duration of response was 13 months, and estimated progression-free and overall survival times were 12 and 17.4 months, respectively. Responding patients had significant increase in polyclonal immunoglobulin M (P = .005), indicating innate immune system activation. Western blot analysis of Bcl-2 protein isolated from myeloma cells before and after G3139 demonstrated a decrease of Bcl-2 levels in three of seven patients compared with six of nine patients using reverse transcriptase polymerase chain reaction.


CONCLUSIONS
G3139, dexamethasone, and thalidomide are well tolerated and result in encouraging clinical responses in relapsed multiple myeloma patients.
Badros
Ashraf Z
AZ
Greenebaum Cancer Center, Department of Pathology, University of Maryland, 22 S Greene St, Baltimore, MD 21201, USA. abadros@umm.edu
Goloubeva
Olga
O
Rapoport
Aaron P
AP
Ratterree
Bashi
B
Gahres
Natalie
N
Meisenberg
Barry
B
Takebe
Naoko
N
Heyman
Meyer
M
Zwiebel
James
J
Streicher
Howard
H
Gocke
Christopher D
CD
Tomic
Dragana
D
Flaws
Jodi A
JA
Zhang
Bin
B
Fenton
Robert G
RG
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015153:Blotting, Western; D003907:Dexamethasone / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage; D012008:Recurrence; D020133:Reverse Transcriptase Polymerase Chain Reaction; D033581:Stem Cell Transplantation; D016019:Survival Analysis; D013792:Thalidomide / Q000008:administration & dosage; D013873:Thionucleotides / Q000008:administration & dosage; D016896:Treatment Outcome
D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D013792:Thalidomide; D003907:Dexamethasone; C408162:oblimersen