Bortezomib, Dexamethasone, and Fibroblast Growth Factor Receptor 3–Specific Tyrosine Kinase Inhibitor in t(4;14) Myeloma

• Published in: Clinical cancer research Vol. 15; no. 2; pp. 520 - 531
• Main Authors: BISPING, Guido, WENNING, Doris, VOLPERT, Sarah, MESTERS, Rolf M, BERDEL, Wolfgang E, KIENAST, Joachim, KROPFF, Martin, GUSTAVUS, Dirk, MÜLLER-TIDOW, Carsten, STELLJES, Matthias, MUNZERT, Gerd, HILBERG, Frank, ROTH, Gerald J, STEFANIC, Martin
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.01.2009
• Subjects: Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Agents, Hormonal - pharmacology; Biological and medical sciences; Boronic Acids - pharmacology; Bortezomib; Cell Line, Tumor; Chromosome aberrations; Chromosomes, Human, Pair 14; Chromosomes, Human, Pair 4; dexamethasone; Dexamethasone - pharmacology; Enzyme Inhibitors - pharmacology; Fibroblast Growth Factor 3 - antagonists & inhibitors; Fibroblast Growth Factor 3 - metabolism; Hematologic and hematopoietic diseases; Humans; Immunodeficiencies. Immunoglobulinopathies; Immunoglobulinopathies; Immunopathology; In Situ Hybridization, Fluorescence; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical genetics; Medical sciences; Multiple Myeloma - genetics; Mutation; Pharmacology. Drug treatments; Protein-Tyrosine Kinases - antagonists & inhibitors; Pyrazines - pharmacology; ras mutation; receptor tyrosine kinase (RTK) inhibitor; t(4;14); Translocation, Genetic; Chromosomal aberration; Antineoplastic agent; Myeloma; Immunoglobulinopathy; Lymphoproliferative syndrome; Protein-tyrosine kinase; Chromosome translocation; Fibroblast growth factor receptor 3; Corticosteroid; Immunopathology; Bortezomib; Dexamethasone; Enzyme; Steroid hormone; Tyrosine kinase inhibitor; Transferases; Enzyme inhibitor; B cell neoplasm; Malignant hemopathy; Lymphoid neoplasm; Abnormal chromosome B4; Analog; Proteasome inhibitor; Dipeptides; Abnormal chromosome D14; Abnormal chromosome; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-1612

Purpose: 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. Experimental Design: 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.