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Advances in Biology and Pathophysiology of Multiple Myeloma PowerPoint Presentation

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Description : Check out this medical PowerPoint presentation titled "Advances in Biology and Pathophysiology of Multiple Myeloma” by Amer G. Rassam, MD.

This medical PowerPoint presentation is about multiple myeloma (MM), a type of cancer that affects plasma cells, which are a type of white blood cell that produces antibodies. In MM, abnormal plasma cells, called myeloma cells, grow uncontrollably in the bone marrow and can cause damage to bone and other tissues.

The exact cause of MM is unknown, but it is believed to be a result of genetic mutations in the plasma cells. Risk factors for MM include older age, male gender, exposure to radiation or certain chemicals, and a family history of the disease.

This presentation throws light on the mechanisms involved in the pathophysiology of MM.

Tags : Pathophysiology of Multiple Myeloma, cancer, Hematology, Hematology PowerPoint presentation

Published on : May 29, 2023 | Views : 1194 | Downloads : 11

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Slide 1-

Advances in Biology and Pathophysiology of Multiple Myeloma Amer G. Rassam, MD
Slide 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
Slide 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
Slide 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
Slide 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
Slide 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
Slide 7-

Age % 0 5 10 15 20 25 30 35 <40 40-49 50-59 60-69 70-79 >80 Age Distribution in Multiple Myeloma
Slide 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)
Slide 9-

Immunophenotype of Multiple Myeloma Marker Features
Slide 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
Slide 11-

Mechanisms of Disease Progression in Monoclonal Gammopathies Kyle RA et al. N Engl J Med. 2004 Oct 28;351(18):1860-73
Slide 12-

Chromosomal Abnormalities in MM Translocations (listed in order of frequency)
Slide 13-

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

Pathogenesis of Multiple Myeloma Two pathways involved in the early pathogenesis of MGUS and MM 50% non-hyperdiploid 50% Hyperdiploid IgH Translocations Infrequent 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
Slide 15-

Pathogenesis of Multiple Myeloma 0 10 20 30 40 50 60 70 80 90 100 MGUS MM PPCL HMCLs Prevelance of IgH Translocations Hideshima et al, Blood, August 2004, 607-618
Slide 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
Slide 17-

Translocations in MM Hideshima et al, Blood, August 2004, 607-618 Primary Secondary 6p21 4p16 16q23 11q13 20q11 90% HMCLs 40% adv MM 15% MM c-myc
Slide 18-

Translocation and Cyclin D (TC) Molecular Classification of MM Bergsagel and Kuehl, Immunol Rev, 2003, 194:96-104
Slide 19-

Cyclin D Expression in Normal and Malignant Plasma Cells PPC BMPC 6p D1 11q13 D1+D2 other maf 4p16 TC1 TC2 TC5 TC3 TC4 D1=Green, D2=Red, D3=Blue Tarte k. et al, Blood. 2002;100:1113-1122. Zhan F. et al, Blood. 2002; 99:1745-1757
Slide 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
Slide 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
Slide 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
Slide 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
Slide 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
Slide 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
Slide 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
Slide 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
Slide 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.
Slide 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
Slide 30-

Critical role for Cyclin D/Rb pathway in MM OFF ON Cyclin D1 Cyclin D2 Cyclin D3 TC1 TC3 TC4 TC5 TC2 11q13 CCND1 6p21 CCND3 Hyperdiploid Cyclin D1 Other FGFR3 4p16 MMSET 16q23 c-maf 20q11 mafB CDK 4, 6 CDK 4, 6 CDK 4, 6 G1 Phase S Phase Rb E2F Rb E2F p15 p16 p18 p19 INK4a INK4d INK4b INK4c
Slide 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
Slide 32-

MM BMSC TNFα TGFβ VEGF IL-6 IL-6 VEGF IGF-1 SDF-1α NF-KB Interaction of MM cells and their BM milieu MEK/ERK GSK-3β FKHR Caspase-9 NF-KB mTOR Bad PKC Akt migration JAK/STAT3 LFA-1 VCAM-1 Fibronectin ICAM-1 NF-KB MUC-1 VLA-4 Adhesion molecules Proliferation Anti-apoptosis Survival Anti-apoptosis Cell cycle Proliferation p27Kip1 Survival Anti-apoptosis Cell cycle PI3-K NF-KB ERK Smad2 Bcl-xL IAP Cyclin-D Bcl-xL MCL-1 MEK/ERK Survival Anti-apoptosis
Slide 33-

Myeloma Cells and BM Microenvironment Bruno et al, The Lancet Oncology, July 2004, 430-442
Slide 34-

Apoptotic Signaling Pathways Velcade ZME-2 Dex ImiDs, Velcade HDAC-I, 2ME-2 TNFα FasL TRAIL JNK Caspase-9 Caspase-8 Caspase-3 PARP Apoptosis IL-6 IGF-1 Smac Cytochrome-c Bid FADD Mitochondria Hideshima et al, Blood, August 2004, 607-618
Slide 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-1α Novel Agents
Slide 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
Slide 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-dioxoolean-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)
Slide 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
Slide 39-

Bruno et al, The Lancet Oncology, July 2004, 430-442 Homoeostasis of Healthy Bone Tissue and MM Bone Disease
Slide 40-

TNFα IL1β Interferon ɣ MIP1 Osteoclast IL6 RANK RANKL Bone Marrow stromal Cells Bone Destruction Osteoclast Precursor Multiple Myeloma Cells IL7
Slide 41-

Bruno et al, The Lancet Oncology, July 2004, 430-442 Effects of Thalidomide on the Myeloma Microenvironment
Slide 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 ILNɣ VEGF bFGF
Slide 43-

Bruno et al, The Lancet Oncology, July 2004, 430-442 Mechanism of Action of Bortezomib Phosphorylation of NFKB inhibitory partner protein IKB leads to degradation of IKB by the proteosome and release of NFKB NFKB 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 NFKB
Slide 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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