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Advances in Biology and Pathophysiology of Multiple Myeloma Amer G. Rassam, MD.

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Presentation on theme: "Advances in Biology and Pathophysiology of Multiple Myeloma Amer G. Rassam, MD."— Presentation transcript:

1 Advances in Biology and Pathophysiology of Multiple Myeloma Amer G. Rassam, MD

2 History of Multiple Myeloma  First case, a London grocer “Thomas Alexander McBean”  Jumped from a cave in 1844  According to Drs. Thomas Watson and William MacIntyre, Mr. McBean had “Mollities et Fragilitas Ossium”  Mr. McBean died on New Year’s day in 1846

3 History of Multiple Myeloma  Urine sample presented to “Henry Bence Jones”  Large amount of protein was found in the sample  The protein has became known as Bence Jones Protein

4 Santiago Ramon Y. Cajal 1852-1934 Paul Gerson Unna 1850-1929 History of Multiple Myeloma In 1890s, Paul Unna and Ramon Cajal identified the plasma cell as a cell type and the cause of Multiple Myeloma

5 History of Multiple Myeloma  In 1873, Rustizky introduced the name Multiple Myeloma  In 1922, Bayne-Jones and Wilson identified 2 distinct groups of Bence Jones protein  In 1956, Korngold and Lipari identified the relationship between Bence Jones protein and serum proteins

6 Epidemiology of Multiple Myeloma  Prevalence (at any one time) : 40000  Incidence: 14000 diagnosed each year  Median age: 65  Median survival: 33 months  M:F 53:47  1.1% of all cancer diagnosis  2% of all cancer deaths

7 Age % 0 5 10 15 20 25 30 35 <4040-4950-5960-6970-79>80 Age Distribution in Multiple Myeloma

8 Monoclonal Gammopathies – Mayo clinic MGUS 62% (659) MM 16% (172) Extramedullary 1% (8) SMM 4% (39) LP 3% (37) AL 8% (90) Other 3% (33) Macro 3% (30)

9 Immunophenotype of Multiple Myeloma CD10 Subset CD19 & CD20 Rarely expressed CD28 & CD86 Occurs with progressive disease CD34 Not expressed by malignant clone CD38 High expression of most but not all malignant cells CD56 (N-CAM) Absent in MGUS and PCL CD138 Syndecan-1 is over expressed MarkerFeatures

10 Long-lived plasma cell Pre-B cell G, A, D, E Lymphoblast Plasmablast Naïve B Cell Short-lived plasma cell Lymph Node Lymphoplasmacyte (memory B Cell) Follicle center Bone Marrow Stimulation with Antigen Somatic Hypermutation of Ig Sequences Isotype Switching :: : :... IgM Normal B-cell Development IgM

11 Mechanisms of Disease Progression in Monoclonal Gammopathies Kyle RA et al. N Engl J Med. 2004 Oct 28;351(18):1860-73

12 Chromosomal Abnormalities in MM Translocations (listed in order of frequency) 14q32 with 11q13 (cyclin D, other new fibroblastic growth factors) 4p16 (FGFR3) 6p25 (Interferon regulatory factor 4) 16q23 (C-MAF transcription factor) 8q24 (C-MYC) 18q21 (BCL-2) 1q with 5, 8, 12, 14, 15, 16, 17, 19q, 21, 22 Losses 6q, 13q Gains 3, 5, 7, 9q, 11q, 12q, 15q, 17q, 18, 19, 21, 22q

13 Chromosome 13 Deletions in MM Shaughnessy J et al, Blood, 2000; 96:1505 12 11 13 21 14 32 31 22 34 33

14 Pathogenesis of Multiple Myeloma Two pathways involved in the early pathogenesis of MGUS and MM 50% non-hyperdiploid50% Hyperdiploid IgH TranslocationsInfrequent IgH Translocations 4p16 FGFR3+ MMSET 11q13 (cyclin D1) 6p21 (cyclin D3) 20q11 (mafB) 16q23 (c-maf) Multiple trisomies of chromosomes 3, 5, 7, 9, 11, 15, 19 and 21 Hideshima et al, Blood, August 2004, 607-618

15 Pathogenesis of Multiple Myeloma 0 10 20 30 40 50 60 70 80 90 100 MGUSMMPPCLHMCLs Prevelance of IgH Translocations Hideshima et al, Blood, August 2004, 607-618

16 Prevalence of IgH Translocations  Lower incidence with MGUS/SMM  de novo MM  Rapid progression of MGUS to MM  Extremely poor prognosis 4p16 or 16q23

17 Translocations in MM Hideshima et al, Blood, August 2004, 607-618 PrimarySecondary 6p21 4p1616q23 11q1320q11 90% HMCLs 40% adv MM 15% MM c-myc

18 Translocation and Cyclin D (TC) Molecular Classification of MM Group Primary translocation Gene(s) at breakpointD-CyclinPloidy Freq of TC in newly diag MM, % TC1 11q13 6p21 CCND1 CCND3 D1 D3NH 15 3 TC2 None D1H37 TC3 None D2H=NH22 TC4 4p16 FGFR3/ MMSETD2NH>H16 TC5 16q23 20q11 c-maf mafBD2NH 5252 Bergsagel and Kuehl, Immunol Rev, 2003, 194:96-104

19 Cyclin D Expression in Normal and Malignant Plasma Cells PPCBMPC6pD111q13D1+D2othermaf4p16 TC1TC2TC5TC3TC4 D1=Green, D2=Red, D3=Blue Tarte k. et al, Blood. 2002;100:1113-1122. Zhan F. et al, Blood. 2002; 99:1745-1757

20 Dysregulation of cyclin D1, D2, D3 “a unifying oncogenic event in MM”  MGUS and MM appear closer to normal PCs than to normal PBs  >30% of cells can be in S phase  Expression level of cyclin D1, D2, D3 mRNA in MM and MGUS is distinctly higher than normal PCs  Expression level of cyclin D2 mRNA is comparable with that expressed in normal proliferating PBs

21 Dysregulation of cyclin D1, D2, D3 “a unifying oncogenic event in MM”  Cyclin D1 is not expressed in normal hemopoitic cells  Cyclin D1 expressed in 40% of MM lacking a t(11;14) translocation  Ig translocations that dysregulate cyclin D1 or D3 occur in about 20% of MM tumors  Therefore, almost all MM tumors dysregulate at least one of the cyclin D genes

22 Progression to Plasma Cell Neoplasia p18 p53 c-myc N, K-RAS FGFR3 NON- HYPER DIPLOID HYPER DIPLOID DEL 13 ?p16 11q13 6p21 16q23 20q11 4p16 Other Primary IgH tx TRISOMY 3, 5, 7, 9, 11, 15, 19, 21 Germinal center B cell MGUS Intramedullary Myeloma Extramedullary Myeloma HMCL Hideshima et al, Blood, August 2004, 607-618

23 Normal Plasma Cell MGUS IgH translocations Intra- medulary myeloma Extra- medullary myeloma Deletion of 13q Chromosomal instability RAS mutations Dysregulation of c-MYC p53 mutations Progression to Plasma Cell Neoplasia

24 The TC Molecular Classification Predicts Prognosis and Response to Therapies Bad prognosis Increased PC Labeling Index Tumor Cells with Abnormal Karyotype Monosomy of chro 13/13q Hypodiploidy Monosomy of chro 17 Activating Mutations of K-Ras t(4;14) TC4 Lack of Cyclin D1 Expression Deletion of p53 t(14;16) TC5

25 The TC Molecular Classification Predicts Prognosis and Response to Therapies t(4;14) translocation (TC 4) Shortened Survival Standard Therapy (42) High-dose Therapy (22) Median OS 26 months Median OS 33 months Fonseca R et al, Blood. 2003; 101:4569-4575 Moreau et al, Blood. 2002; 100:1579-1583

26 t(14;16) translocation (TC 5) Shortened Survival (worse Prognosis) Standard Therapy (15) Median OS 16 months The TC Molecular Classification Predicts Prognosis and Response to Therapies Fonseca R et al, Blood. 2003; 101:4569-4575

27 The TC Molecular Classification Predicts Prognosis and Response to Therapies t(11;14) translocation (TC 1) Better Survival Standard Therapy (53) High-dose Therapy (26) Median OS 50 months Median OS 80 months Fonseca R et al, Blood. 2003; 101:4569-4575 Moreau et al, Blood. 2002; 100:1579-1583

28 The TC Molecular Classification Predicts Prognosis and Response to Therapies  The TC classification may be clinically useful way to classify patients into groups that have distinct subtypes of MM (and MGUS) tumors.  The TC classification identifies clinically important molecular subtypes of MM with different prognosis and with unique responses to different treatments.

29 The TC Molecular Classification Predicts Prognosis and Response to Therapies  High dose therapy and TC1  Microenvironment-directed therapy and TC2  FGFR3 inhibitor and TC4  maf dominant-negative and TC5

30 Critical role for Cyclin D/Rb pathway in MM OFF ON Cyclin D1Cyclin D2Cyclin D3 TC1 TC3TC4TC5TC2 11q13 CCND1 6p21 CCND3 Hyperdiploid Cyclin D1 Other FGFR3 4p16 MMSET 16q23 c-maf 20q11 mafB CDK 4, 6 G1 Phase S Phase Rb E2F Rb E2F p15 p16 p18 p19 INK4a INK4d INK4b INK4c pp p p

31 Silencing of CDK inhibitor mRMA expression might be reversed Targeting Cyclin D Targeting the genes Directly dysregulated By translocation HDAC Inhibitors DNA methyl Transferase inhibitor Novel Therapeutic Strategies targeting Genetic Abnormalities Desferroxamine Selective CDK inhibitors Targeting FGFR3 by monoclonal antibodies Targeting FGFR3 by selective tyrosine kinase inhibitor

32 MM BMSC TNFα TGFβ VEGF IL-6 IL-6 VEGF IGF-1 SDF-1α NF -K B Interaction of MM cells and their BM milieu MEK/ERK GSK-3 β FKHR Caspase-9 NF -K B mTOR Bad PKC Akt migration JAK/STAT3 LFA-1 VCAM-1 Fibronectin ICAM-1 NF -K B MUC-1 VLA-4 Adhesion molecules Proliferation Anti-apoptosis Survival Anti-apoptosis Cell cycle Proliferation p27 Kip1 Survival Anti-apoptosis Cell cycle PI3-K NF -K B ERK Smad2 Bcl-xL IAP Cyclin-D Bcl-xL MCL-1 MEK/ERK Survival Anti-apoptosis

33 Myeloma Cells and BM Microenvironment Bruno et al, The Lancet Oncology, July 2004, 430-442

34 Apoptotic Signaling Pathways Velcade ZME-2 Dex ImiDs, Velcade HDAC-I, 2ME-2 TNFα FasL TRAIL JNK Caspase-9Caspase-8 Caspase-3 PARP Apoptosis IL-6 IGF-1 SmacCytochrome-c Bid FADD Mitochondria Hideshima et al, Blood, August 2004, 607-618

35 Novel biologically based therapies targeting MM cells and the BM microenvironment A D C B Angiogenesis Adhesion Molecule Drug Resistance Proliferation Apoptosis Growth Arrest Inhibition of Adhesion Inhibition of Cytokines bFGF VEGF IL-6 IGF-1 VEGF SDF-1 α Novel Agents

36 Novel Agents for Myeloma  Targeting both MM cells and interaction of MM cells with the BM microenvironment  Targeting circuits mediating MM cell growth and survival  Targeting the BM microenvironment  Targeting cell surface receptors

37 Novel Agents for Myeloma  Thalidomide and its analogs (Revlimid)  Proteasome inhibitor (Bortezomib)  Arsenic trioxide  2-Methoxyestradiol (2-ME2)  Lysophosphatidic acid acyltransferase- β inhibitor  Triterpinoid 2-cyano-3, 12-dio xoolean-1, 9-dien- 28- oic acid (CDDO)  N-N-Diethl-8, 8-dipropyl-2-azaspiro [4.5] decane-2-propanamine (Atiprimod) Targeting both MM cells and their interaction with BM microenvironment Targeting circuits mediating MM cell growth and survival  VEGF receptor tyrosine kinase inhibitor (PTK787/ZK222584, GW654652)  Farnesyltransferase inhibitor  Histone deacetylase inhibitor (SAHA, LAQ824)  Heat shock protein-90 inhibitor (Geldanamycin,17-AAG)  Telomerase inhibitor (Telomestatin)  bcl-2 antisense oligonucleotide (Genasense)  Inosine monophophate dehydrogenase (VX-944)  Rapamycin Targeting cell surface receptors Targeting the bone marrow microenvironment  IĸB kinase (IKK) inhibitor (PS-1145)  p38 MAPK inhibitor (VX-745, SCIO-469)  TFG- β inhibitor (SD-208)  TNF related apoptosis-inducing ligand (TRAIL) / Apo2 ligand  IGF-1 receptor inhibitor ( ADW)  HMG-CoA reductase inhibitor (statins)  Anti-CD20 antibody (Rituximab)

38 Proposed Mechanism of Action of Drugs in Targeting Myeloma Cells and BM Microenvironment Kyle RA et al. N Engl J Med. 2004 Oct 28;351(18):1860-73

39 Bruno et al, The Lancet Oncology, July 2004, 430-442 Homoeostasis of Healthy Bone Tissue and MM Bone Disease

40 TNFα IL1β Osteoprotegerin (OPG) T cell Interferon ɣ MIP1 Osteoclast IL6 RANK RANKL Bone Marrow stromal Cells Bone DestructionOsteoclast Precursor Multiple Myeloma Cells IL7 Osteoblast

41 Bruno et al, The Lancet Oncology, July 2004, 430-442 Effects of Thalidomide on the Myeloma Microenvironment

42 Proposed Action of Thalidomide in Myeloma Mutiple Myeloma Cells T Lymphocytes Bone Marrow Stromal Cells Modulation of Cytokines Bone Marrow Vessels Cytotoxicity of NK Cells Modulation of Immune System Direct Action Inhibition of Angiogenesis VEGF IL6 TNFα IL1β IL2 ILN ɣ VEGF bFGF

43 Bruno et al, The Lancet Oncology, July 2004, 430-442 Mechanism of Action of Bortezomib  Phosphorylation of NF K B inhibitory partner protein I K B leads to degradation of I K B by the proteosome and release of NF K B  NF K B migrates into the nucleus to induce arrest of apoptosis and expression of adhesion molecule  Affinity of Bortezomib for the proteosome inhibits protein degradation, and prevents nuclear translocation of NF K B

44 Bruno et al, The Lancet Oncology, July 2004, 430-442 Mechanism of Action of Arsenic Trioxide  Mutated P53: Arsenic trioxide triggers the caspase cascade by activation of caspases 8 and 10  Functional P53: The cascade is activated through the mitochondrial apoptotic pathway and the activation of caspase 9

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