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Development of Novel Therapies for Multiple Myeloma and Waldenstrom’s Macroglobulinemia Kenneth C. Anderson, M.D. Jerome Lipper Multiple Myeloma Center Dana-Farber Cancer Institute Harvard Medical School Historical Perspective of Multiple Myeloma Therapies Proteasome High-dose therapy inhibitors ABMT with autologous Other immuno- stem cell support modulatory agents. HDACs VAD Bisphosphonates High-dose melphalan High-dose Thalidomide dexamethasone Oral melphalan and prednisone 1962 1983 1984 1986 1996 1999 2000+ Targeting Growth, Survival, and Drug Resistance of MM in BM Microenvironment MM migration SC GSK-3 CD40 FKHR PKC Survival Caspase-9 Anti-apoptosis Cell surface Akt NF-B Cell cycle mTOR targets PI3-K Bad Survival Bcl-xL JAK/STAT3 Anti-apoptosis Mcl-1 BAFF-R Raf MEK/ERK proliferation VEGFR Bcl-xL Survival NF-B IAP Anti-apoptosis Cytokines Cyclin-D Cell cycle IL-6, VEGF IGF-1, SDF-1 TNF BAFF, APRIL MEK/ERK Proliferation TGF BSF-3 p27Kip1 Anti-apoptosis VEGF Smad, ERK Adhesion cytokines NF-B adhesion LFA-1 molecules ICAM-1 NF-B MUC-1 BMSC NF-B VCAM-1 Fibronectin VLA-4 Hideshima T and Anderson KC. Nat Rev Cancer 2007, Mechanisms Mediating Anti-MM Activity of Bortezomib Anti-Angiogenic & ER-Stress Induction Apoptosis Anti-Osteoclastic Actvity Caspase-12 cleavage;  JNK; Caspases & PARP cleavage;  Migration, VEGF,  phospo-PERK;  ROS;  ∆m Proangiogenic MMP-9, &  GADD-153, ATF4, GRP 78, &  Cyto-c & Smac release;  IAPs; Caveolin-1; XBP-1 splicing  mitochondrial Ca+2 influx; Osteoclastogenesis via  Bid cleavage, Fas & FasL, BH-3 MIP1, BAFF only proteins: Bim, Bik, & NOXA  Osteoblast formation Heat Shock Proteins Growth & Survival & DNA Repair NF-B, MAPK,JAK/STAT Bortezomib  Heat Shock Proteins-27, -70, IGF-1/IL-6.  PI3K-Akt 90;  DNA-PK Microenvironment Cell-Cycle  MM-BMSC’s interaction; Cdk inhibitors: Proteasome  ICAM, VCAM, V3  P21 & p27, p53 IGF-1, IL-6, BAFF,RANKL Cyclins: D1, E1, A, B.  Chymotrypsin- and Caspase- like proteasome activities;  Mono-ubiquitination;  26S Proteasome subunits Lenalidomide in Myeloma C MM cells IL-6 TNF B IL-1 A Bone Marrow ICAM-1 Stromal Cells Bone Marrow Vessels NFAT IL-2 PKC IL-2 IFN  NK Cells VEGF PI3K CD28 NK-T bFGF Cells CD8+ T Dendritic Cells D E Cells Mitsiades et al. Blood 99: 4525, 2002 Hideshima et al. Blood 96: 2943, 2000 Lentzsch et al Cancer Res 62: 2300, 2002 Davies et al. Blood 98: 210, 2001 LeBlanc R et al. Blood 103: 1787, 2004 Gupta et al. Leukemia 15: 1950, 2001 Hayashi T et al. Brit J Hematol 128: 192, 2005 Integration of Novel Therapy Into Myeloma Management Bortezomib, Lenalidomide, Thalidomide, Doxil, Carfilzomib, Pomalidamide, Panobinostat Target MM in the BM microenvironment to overcome conventional drug resistance in vitro and in vivo Effective in relapsed/refractory, relapsed, induction, consolidation, and maintenance therapy Eleven FDA approvals and median survival prolonged from 3-4 to 6-7 years, with additional prolongation from maintenance New approaches needed to treat and ultimately prevent relapse Chromosomes and Prognosis in Multiple Myeloma For conventional low and high dose theapy: Nonhyperdiploid worse prognosis than hyperdiploid t(11;14), hyperdiplody -standard risk t(4;14), t(14;16),t(14;20), del(17p), del(13q14)-high risk For novel treatments Bortezomib, but not lenalidomide, can at least partially overcome t(4;14), del(13q14) del(17p) p53 remains high risk Combinations in the Upfront Treatment of MM Stewart AK, Richardson PG, San Miguel JF Blood 2009

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Raf. Adhesion. Targeting Growth, Survival, and Drug Resistance of MM .. ORR (≥PR) of 18%, plus 2% MR and 30% SD, including relapse post. Bortezomib . Advances in the Biology of Waldenstrom's Macroglobulinemia. WM.
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