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Management of Multiple Myeloma Irza Wahid Subdivision of Hematology – Medical Oncology Departement of Internal Medicine Medical Faculty, Andalas University.

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Presentation on theme: "Management of Multiple Myeloma Irza Wahid Subdivision of Hematology – Medical Oncology Departement of Internal Medicine Medical Faculty, Andalas University."— Presentation transcript:

1 Management of Multiple Myeloma Irza Wahid Subdivision of Hematology – Medical Oncology Departement of Internal Medicine Medical Faculty, Andalas University

2 Blok Muskuloskeletal Bone Metastases

3 PA-3 Disease prevalence, Bone mets. Median U.S. (in thousands)incidence (%) survival (mo) Myeloma 75 - 10070 - 9524 Renal 19820 - 2512 Melanoma 46714 - 456 Bladder 582406 - 9 Thyroid 2076048 Lung 38630 - 407 Breast 1,99365 - 7524 Prostate 98465 - 7536 Clinical Importance and Prognosis of Bone Metastases NCI, 197; International Myeloma Foundation, 2001.

4 Multiple Myeloma Definition B-cell malignancy characterised by abnormal proliferation of plasma cells to produce a monoclonal immunoglobulin ( M protein ) Definition B-cell malignancy characterised by abnormal proliferation of plasma cells to produce a monoclonal immunoglobulin ( M protein )

5 5 Pluripot ent Stem Cell Myeloid Stem Cell Lymphoid Stem Cell CFU-T CFU-B CFU-Eosin CFU-Bas CFU- GM CFU-MEG BFU-E T-Cell B-Cell eosinophil basophil neutrophil platelets monocyte macrophage erythrocyte Genesis of Blood Products Copyright © 2006 by Elsevier, Inc. Hemocytoblast CFU-L CFU-M Sel PlasmaIg

6 Greenlee RT. CA Cancer J Clin 2001;51:15. Bergsagel DE. Blood 1999;94:1174 MM Epidemiology 19,900 new cases per yr, 50,000 total cases, 2% cancer deaths in U.S. Higher incidence in African Americans, Pacific Islanders Median age 71 yrs Exposure to radiation, petroleum products, pesticides & Agent Orange 19,900 new cases per yr, 50,000 total cases, 2% cancer deaths in U.S. Higher incidence in African Americans, Pacific Islanders Median age 71 yrs Exposure to radiation, petroleum products, pesticides & Agent Orange

7 Statistics Second most prevalent blood cancer Approximately 1% of all cancers and 2% of all cancer deaths. 45,000 currently have multiple myeloma 14,600 new cases of myeloma each year. Responsible for more than 10,000 deaths in the United States annually. Second most prevalent blood cancer Approximately 1% of all cancers and 2% of all cancer deaths. 45,000 currently have multiple myeloma 14,600 new cases of myeloma each year. Responsible for more than 10,000 deaths in the United States annually. http://www.multiplemyeloma.org/about_myeloma/2.03.asp

8 How Plasma Cells Work Develop from stem cells in bone marrow Stem cells develop into B cells (B lymphocytes) Antigens enter body then B cells develop into plasma cells Produce antibodies Develop from stem cells in bone marrow Stem cells develop into B cells (B lymphocytes) Antigens enter body then B cells develop into plasma cells Produce antibodies

9 Normal Cell (5%)

10 Myeloma Cells (10%)

11 What Causes Myeloma Cells To Grow? Adhesion molecules Stromal cells Interactions: –Cytokins (chemical messengers) – Growth factors that promote angiogenesis – Inactivated immune system Adhesion molecules Stromal cells Interactions: –Cytokins (chemical messengers) – Growth factors that promote angiogenesis – Inactivated immune system

12 CLINICAL MANIFESTASION Clinical manifestations are related to malignant behavior of plasma cells and abnormalities produce by M protein plasma cell proliferation: - multiple osteolytic bone lesions - hypercalcemia - bone marrow suppression ( pancytopenia ) monoclonal M protein - decreased level of normal immunoglobulins - hyperviscosity Clinical manifestations are related to malignant behavior of plasma cells and abnormalities produce by M protein plasma cell proliferation: - multiple osteolytic bone lesions - hypercalcemia - bone marrow suppression ( pancytopenia ) monoclonal M protein - decreased level of normal immunoglobulins - hyperviscosity

13 Symptoms Anemia Fatigue Bone pain –Back –Ribs Unexplained bone fractures Repeated infections –Pneumonia –Bladder and kidney infection –Urinary tract infection Weight loss Weakness and numbness in limbs Anemia Fatigue Bone pain –Back –Ribs Unexplained bone fractures Repeated infections –Pneumonia –Bladder and kidney infection –Urinary tract infection Weight loss Weakness and numbness in limbs

14 Symptoms Abnormal proteins –Blood and urine –Polyclonal to Monoclonal proteins High level of calcium in blood –Excessive thirst and urination –Sleepiness –Constipation –Nausea –Loss of appetite –Mental confusion Abnormal proteins –Blood and urine –Polyclonal to Monoclonal proteins High level of calcium in blood –Excessive thirst and urination –Sleepiness –Constipation –Nausea –Loss of appetite –Mental confusion

15 Signs & Symptoms in 1027 Newly Diagnosed Myeloma Patients 0 0 10 20 30 40 50 60 70 80 Bone lesions Fatigue Cr >2 mg/dL Ca >11 mg/dL Wt loss (>9 kg) % patients 79 Hb<12 g/dL 73 Bone pain 66 32 13 19 12 Kyle RA. Mayo Clin Proc 2003;78:21-33

16 Screening and Diagnosis Blood and urine tests X-rays Magnetic Resonance Imaging (MRI) Computerized Tomography (CT) Bone marrow examination Blood and urine tests X-rays Magnetic Resonance Imaging (MRI) Computerized Tomography (CT) Bone marrow examination

17 Diagnostic Criteria for Multiple Myeloma Major criteria I. Plasmacytoma on tissue biopsy II. Bone marrow plasma cell > 30% III. Monoclonal M spike on electrophoresis IgG > 3,5g/dl, IgA > 2g/dl, light chain > 1g/dl in 24h urine sample Minor criteria a. Bone marrow plasma cells 10-30% b. M spike c. Lytic bone lesions d. Normal IgM < 50mg, IgA < 100mg, IgG < 600mg/dl Major criteria I. Plasmacytoma on tissue biopsy II. Bone marrow plasma cell > 30% III. Monoclonal M spike on electrophoresis IgG > 3,5g/dl, IgA > 2g/dl, light chain > 1g/dl in 24h urine sample Minor criteria a. Bone marrow plasma cells 10-30% b. M spike c. Lytic bone lesions d. Normal IgM < 50mg, IgA < 100mg, IgG < 600mg/dl

18 Diagnostic Criteria for Multiple Myeloma Diagnosis: I + b, I + c, I + d II + b, II + c, II + d III + a, III + c, I II + d a + b + c, a +b + d Diagnosis: I + b, I + c, I + d II + b, II + c, II + d III + a, III + c, I II + d a + b + c, a +b + d

19 Staging of Multiple Myeloma Clinical staging is based on level of haemoglobin, serum calcium, immunoglobulins and presence or not of lytic bone lesions subclassification A - creatinine < 2mg/dl B - creatinine > 2mg/dl Clinical staging is based on level of haemoglobin, serum calcium, immunoglobulins and presence or not of lytic bone lesions subclassification A - creatinine < 2mg/dl B - creatinine > 2mg/dl

20 Myeloma Prognostic Factors Serum  2 microglobulin Cytogenetics - del13 or 13q-, t(4;14), 17p-, hypodiploid C-reactive protein LDH Plasmablastic morphology Peripheral blood plasma cells Gene expression profile Serum  2 microglobulin Cytogenetics - del13 or 13q-, t(4;14), 17p-, hypodiploid C-reactive protein LDH Plasmablastic morphology Peripheral blood plasma cells Gene expression profile

21 Incidence of Chromosomal Abnormalities in MM Genomic AberrationsIncidence of aberration Del (13)48% Del (17p)11% t(4;14) (p16;q32)14% Hyperdiploidy39% t(11;14) (q13;q32)21% n = 1064 patients Chromosomal changes observed in 90% of patients n = 1064 patients Chromosomal changes observed in 90% of patients

22 International Staging System (ISS) for Symptomatic Myeloma International Staging System (ISS) for Symptomatic Myeloma *β2m < 3.5 mg/L and albumin < 3.5 g/dL or β2m 3.5 - < 5.5 mg/L, any albumin *β2m < 3.5 mg/L and albumin < 3.5 g/dL or β2m 3.5 - < 5.5 mg/L, any albumin Greipp et al. J Clin Oncol 2005; 23: 3412-20 StageCriteria Median Survival (mo) I β2m < 3.5 mg/L albumin ≥ 3.5 g/dL 62 II*Not stage I or III44 IIIβ2m ≥ 5.5 mg/L29

23 Kyle RA and Rajkumar SV. Cecil Textbook of Medicine, 22nd Edition, 2004 Normal Monoclonal Protein in Myeloma Serum Protein Electrophoresis

24 Distribution of Monoclonal Proteins M protein found in serum or urine or both at time of diagnosis: 97% Serum M spike by protein electrophoresis: 80% Abnormal serum immunofixation: 93% Abnormal urine immunofixation: 75% Non-secretory myeloma: 3% M protein found in serum or urine or both at time of diagnosis: 97% Serum M spike by protein electrophoresis: 80% Abnormal serum immunofixation: 93% Abnormal urine immunofixation: 75% Non-secretory myeloma: 3%

25 Malignant Plasma Cells in Marrow

26 Normal Bone Biology Bone is always in an active state of remodeling (build up/break down) Resorption: stimulated osteoclasts erode bone, creating a cavity Reversal: bone surface is prepared for osteoblasts to begin forming bone Formation: osteoblasts replace resorbed bone and fill the cavity with new bone Resting: bone surface rests until a new remodeling cycle begins Bone is always in an active state of remodeling (build up/break down) Resorption: stimulated osteoclasts erode bone, creating a cavity Reversal: bone surface is prepared for osteoblasts to begin forming bone Formation: osteoblasts replace resorbed bone and fill the cavity with new bone Resting: bone surface rests until a new remodeling cycle begins Adapted from Novert's Pharmaceuticals

27 Vicious cycle of Bone Metastases Mineralized bone matrix Tumor Cells in Bone Osteoblasts New bone Osteoclasts Osteolytic factors RANKL PTH-rp Interleukins 1,6,8 TNFs M-CSF Osteoblastic factors Endothelin-1 Fibroblast growth factor Bone morphogenic proteins Insulin-like growth factors Bone-derived tumor growth factors Transforming growth factor  Insulin-like growth factors Fibroblast growth factors Platelet-derived growth factor Bone morphogenic proteins Derived from Roodman GD. N Engl J Med. 2004;350:1655-1664.

28 Osteolytic metastases Tumor cells produce growth factors that stimulate bone destruction i.e. RANK ligand Osteoclasts are activated and break down bone Osteoblasts cannot build bone back fast enough Decreased bone density and strength; high risk for fracture Tumor cells produce growth factors that stimulate bone destruction i.e. RANK ligand Osteoclasts are activated and break down bone Osteoblasts cannot build bone back fast enough Decreased bone density and strength; high risk for fracture Patel, B. and DeGroot, H. Orthopedics Journal. 2001;24:612-7.

29 Osteoblastic Metastasis Osteoblasts are stimulated by tumors to lay down new bone Bone becomes abnormally dense and stiff Paradoxically bones are also at risk of breaking Osteoblasts are stimulated by tumors to lay down new bone Bone becomes abnormally dense and stiff Paradoxically bones are also at risk of breaking

30 Bone Imaging in MM Skeletal radiography is the primary diagnostic test to detect destructive bony lesions in multiple myeloma MRI is useful in assessing whether spinal compression fractures are due to a focal mass or from osteopenia due to increased osteolysis PET scans can be used to detect soft tissue or bone metastases Skeletal radiography is the primary diagnostic test to detect destructive bony lesions in multiple myeloma MRI is useful in assessing whether spinal compression fractures are due to a focal mass or from osteopenia due to increased osteolysis PET scans can be used to detect soft tissue or bone metastases Angtuaco EJ et al. Radiology. 2004;231:11-23.

31 Treatment Options Goals: –Attack the cancer –Strengthen the bone –Reduce symptoms Includes: –Systemic therapy –Local therapy Goals: –Attack the cancer –Strengthen the bone –Reduce symptoms Includes: –Systemic therapy –Local therapy

32 Clearly not a transplant candidate Can include melphalan- based combinations Potential transplant candidate Non-alkylator based induction Stem cell harvest Initial Approach to Treatment

33 Therapy Options: NonTransplant Candidate Melphalan + Prednisone (MP) Melphalan + Prednisone + Thalidomide (MPT) Dexamethasone (Dex) Thalidomide + Dexamethasone (Thal/Dex) Lenolidomide + Dexamethasone (Rev/Dex) Bortezomib +/- Dexamethasone (Vel/Dex) Melphalan + Prednisone (MP) Melphalan + Prednisone + Thalidomide (MPT) Dexamethasone (Dex) Thalidomide + Dexamethasone (Thal/Dex) Lenolidomide + Dexamethasone (Rev/Dex) Bortezomib +/- Dexamethasone (Vel/Dex) NCCN Practice Guideline-v.2.2008

34 Alternative chemotherapy –M2 ( Vincristine, Melphalan, Cyclophosphamid, BCNU, Prednisone) –VAD (Vincristin, Adriamycin, Dexamethasone) Response rate 50-60% patients Long term survival 5-10% patients Alternative chemotherapy –M2 ( Vincristine, Melphalan, Cyclophosphamid, BCNU, Prednisone) –VAD (Vincristin, Adriamycin, Dexamethasone) Response rate 50-60% patients Long term survival 5-10% patients

35 Bortezomib (Velcade ® ) Reversible inhibitor of chymotrypsin- like activity of 26-S proteasome Prevents proteolysis of ubiquitinated proteins & can lead to apoptosis of tumor cells Dosing: 1.3 mg/m2 IV bolus d 1, 4, 8, & 11 (21-d treatment cycle) for a maximum of 8 cycles FDA approved for MM that has relapsed after ≥1 prior standard therapies Reversible inhibitor of chymotrypsin- like activity of 26-S proteasome Prevents proteolysis of ubiquitinated proteins & can lead to apoptosis of tumor cells Dosing: 1.3 mg/m2 IV bolus d 1, 4, 8, & 11 (21-d treatment cycle) for a maximum of 8 cycles FDA approved for MM that has relapsed after ≥1 prior standard therapies

36 Systemic Therapies Pain control –Pain medication Tylenol, NSAIDs (ibuprofen), narcotics, steroids Success can be limited by side effects –Radiopharmaceuticals Strontium-89 and samarium-153: radioactive particles travel directly to tumor in bone Can reduce pain refractory to other measures Infrequently used Pain control –Pain medication Tylenol, NSAIDs (ibuprofen), narcotics, steroids Success can be limited by side effects –Radiopharmaceuticals Strontium-89 and samarium-153: radioactive particles travel directly to tumor in bone Can reduce pain refractory to other measures Infrequently used

37 Systemic Therapies: Bisphosphonates Bind to and inhibit osteoclast action –Inhibit bone breakdown –Prevent bone damage –Improve bone density and strength Recommended for almost everyone with cancer bone metastases Bind to and inhibit osteoclast action –Inhibit bone breakdown –Prevent bone damage –Improve bone density and strength Recommended for almost everyone with cancer bone metastases

38 Thank You


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