Bortezomib, dexamethasone, and fibroblast growth factor receptor 3-specific tyrosine kinase inhibitor in t(4;14) myeloma.
OBJECTIVE
Novel drugs including targeted approaches have changed treatment paradigms for multiple myeloma (MM) and may also have therapeutic potential in the poor-prognosis t(4;14) subset; t(4;14) results in overexpressed and activated fibroblast growth factor receptor 3 (FGFR3). Blocking this receptor tyrosine kinase (RTK) induces apoptosis in t(4;14)+ MM cells and decreases adhesion to bone marrow stromal cells (BMSC). Using combinations of novel drugs, we investigated potential enhancement of single-agent activities within the tumor cells, targeting of the marrow micromilieu, or circumvention of drug resistance in t(4;14)+ MM.


METHODS
We tested effects on apoptosis and related signaling pathways in the t(4;14)+ MM subset, applying drug combinations including a FGFR3 tyrosine kinase inhibitor (RTKI), the proteasome inhibitor bortezomib, and dexamethasone.


RESULTS
RTKI, bortezomib, and dexamethasone were active as single agents in t(4;14)+ MM. RTK inhibition triggered complementary proapoptotic pathways (e.g., decrease of Mcl-1, down-regulation of p44/42 mitogen-activated protein kinase, and activation of proapoptotic stress-activated protein/c-Jun NH(2)-terminal kinases). Synergistic or additive effects were found by combinations of RTKI with dexamethasone or bortezomib. In selected cases of t(4;14)+ MM, triple combinations were superior to dual combinations tested. Prevention from MM cell apoptosis by BMSC or exogenous interleukin-6 was circumvented by drug combinations. In t(4;14)+, N-ras-mutated NCI-H929 cells, resistance to RTKI was overcome by addition of dexamethasone. Notably, the combination of RTKI and dexamethasone showed additive proapoptotic effects in bortezomib-insensitive t(4;14)+ MM.


CONCLUSIONS
Combining novel drugs in poor-prognosis t(4;14)+ MM should take into account at least bortezomib sensitivity and probably Ras mutational status.
Bisping
Guido
G
Department of Medicine/Hematology and Oncology, University of Muenster, Muenster, Germany.
Wenning
Doris
D
Kropff
Martin
M
Gustavus
Dirk
D
Müller-Tidow
Carsten
C
Stelljes
Matthias
M
Munzert
Gerd
G
Hilberg
Frank
F
Roth
Gerald J
GJ
Stefanic
Martin
M
Volpert
Sarah
S
Mesters
Rolf M
RM
Berdel
Wolfgang E
WE
Kienast
Joachim
J
D000970:Antineoplastic Agents / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002883:Chromosomes, Human, Pair 14; D002894:Chromosomes, Human, Pair 4; D003907:Dexamethasone / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051518:Fibroblast Growth Factor 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009101:Multiple Myeloma / Q000235:genetics*; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011719:Pyrazines / Q000494:pharmacology*; D014178:Translocation, Genetic
D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D051518:Fibroblast Growth Factor 3; D011719:Pyrazines; D000069286:Bortezomib; D003907:Dexamethasone; D011505:Protein-Tyrosine Kinases