Relapsed/Refractory Multiple Myeloma: Defining Refractory Disease and Identifying Strategies to Overcome Resistance David S. Siegel Seminars in Hematology

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Relapsed/Refractory Multiple Myeloma: Defining Refractory Disease and Identifying Strategies to Overcome Resistance David S. Siegel Seminars in Hematology Volume 49, Pages S3-S15 (July 2012) DOI: 10.1053/j.seminhematol.2012.05.005 Copyright © 2012 Terms and Conditions

Figure 1 The role of the bone marrow microenvironment in multiple myeloma. Abbreviations: bFGF, basic fibroblast growth factor; CAM-DR, cell adhesion–mediated drug resistance; DKK1, Dickkopf-related protein 1; GSK-3β, glycogen synthase kinase 3β; HGF, hepatocyte growth factor; ICAM-1, intercellular adhesion molecule 1; IGF, insulin-like growth factor 1; IL, interleukin; JAK/STAT3, Janus kinase/signal transducer and activator of transcription 3; LFA-1, leukocyte function–associated antigen 1; MEK/ERK, Ras/Raf/mitogen-activated protein kinase kinase/extracellular signal–regulated kinase; MIP-1α, macrophage inflammatory protein 1α; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor κB; OPG, osteoprotegerin; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; RANK, receptor activator of NF-κB; RANKL, RANK ligand; SDF-1α, SC-derived factor 1α; TGF-β, transforming growth factor β; TNF-α, tumor necrosis factor α; VCAM-1, vascular cell–adhesion molecule 1; VEGF, vascular endothelial growth factor; VLA-4, very late antigen 4. Reprinted with permission from Anderson KC. Annu Rev Pathol 2011.51 Permission conveyed through the Copyright Clearance Center Inc. Seminars in Hematology 2012 49, S3-S15DOI: (10.1053/j.seminhematol.2012.05.005) Copyright © 2012 Terms and Conditions

Figure 2 Model for the multistep molecular pathogenesis of multiple myeloma. Abbreviations: BLIMP1, B lymphocyte-induced maturation protein; BRAF, v-Raf murine sarcoma viral oncogene homolog B1; DEL, deletion; DEPTOR, DEP domain containing MTOR-interacting protein; DIS3, exosome complex exonuclease RRP44; FAM46C, family with sequence similarity 46, member C; FGFR3, fibroblast growth factor receptor 3; IRF4, interferon regulatory factor 4; K-RAS, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; LRRK2, leucine-rich repeat kinase 2; MGUS, monoclonal gammopathy of undetermined significance; myc, v-myc myelocytomatosis viral oncogene homolog; NF-κβ, nuclear factor kappaB; N-RAS, neuroblastoma RAS viral (v-ras) oncogene homolog; p18, protein 18; p53, protein 53; PI3K/AKT, phosphatidyl inositol 3-kinase/protein kinase B; PIK3CA, phosphatidyl inositol 3-kinase catalytic subunit; PTEN, phosphatase and tensin homolog, RB, retinoblastoma protein; RNA, ribonucleic acid; TLC, translocation; XBP1, X-box binding protein 1. From Chesi M. Hematology Am Soc Hematol Educ Program 2011.91 Copyright 2011. Reproduced with permission of the American Society of Hematology (ASH). Permission conveyed via the Copyright Clearance Center, Inc. Seminars in Hematology 2012 49, S3-S15DOI: (10.1053/j.seminhematol.2012.05.005) Copyright © 2012 Terms and Conditions