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

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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."— 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 Clinical Importance and Prognosis of Bone Metastases
Disease prevalence, Bone mets. Median U.S. (in thousands) incidence (%) survival (mo) Myeloma Renal Melanoma Bladder Thyroid Lung Breast 1, Prostate 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 )

5 Genesis of Blood Products
Pluripotent Stem Cell Myeloid Stem Cell Lymphoid 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 CFU-L Sel Plasma Ig Hemocytoblast CFU-M Copyright © 2006 by Elsevier, Inc.

6 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 Greenlee RT. CA Cancer J Clin 2001;51:15. Bergsagel DE. Blood 1999;94:1174

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.

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

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

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 Unexplained bone fractures
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 High level of calcium in blood
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
10 20 30 40 50 60 70 80 Bone lesions Fatigue Cr >2 mg/dL Ca >11 Wt loss (>9 kg) % patients 79 Hb<12 g/dL 73 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

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

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

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

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

21 Incidence of Chromosomal Abnormalities in MM
Genomic Aberrations Incidence of aberration Del (13) 48% Del (17p) 11% t(4;14) (p16;q32) 14% Hyperdiploidy 39% t(11;14) (q13;q32) 21% n = 1064 patients Chromosomal changes observed in 90% of patients

22 International Staging System (ISS) for Symptomatic Myeloma
Stage Criteria Median Survival (mo) I β2m < 3.5 mg/L albumin ≥ 3.5 g/dL 62 II* Not stage I or III 44 III β2m ≥ 5.5 mg/L 29 *β2m < 3.5 mg/L and albumin < 3.5 g/dL or β2m < 5.5 mg/L, any albumin Greipp et al. J Clin Oncol 2005; 23:

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

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%

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 Adapted from Novert's Pharmaceuticals

27 Vicious cycle of Bone Metastases
CORE Tumor Cells in Bone 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 Osteolytic factors RANKL PTH-rp Interleukins 1,6,8 TNFs M-CSF Pathogenesis of Osteoblastic Bone Metastases Some cancer cells produce soluble paracrine factors (ie, insulin-like growth factor [IGF], fibroblast growth factor [FGF], and bone morphogenic protein [BMP]), causing excessive osteoblast activation Production of endothelin-1 (ET-1) by tumor cells appears to play a central role in stimulating osteoblast activity that results in abnormal bone formation and inducing the subsequent release of osteoblastic growth factors that stimulate tumor cell growth2,3 Osteoblastic metastatic tumor cells release humoral factors, such as PTH-RP and interleukins -6, -8, and -11 that stimulate osteoclastic recruitment and differentiation1 Osteoclastic activity leads to the release of growth factors (ie, TGF-) from bone that also stimulate tumor cell growth, perpetuating a vicious cycle of excessive bone resorption Osteoblastic activation leads to the release of unidentified osteoblastic growth factors that stimulate tumor cell growth, contributing to the perpetual cycle of abnormal bone formation Of note, in both osteoclastic and osteoblastic bone metastases, osteoclasts are important and make a very likely target for treatment Osteoblasts Osteoclasts New bone Mineralized bone matrix Derived from Roodman GD. N Engl J Med. 2004;350: References: 1. Saad F, Schulman CC. Role of bisphosphonates in prostate cancer. Eur Urol. 2004;45:26-34. 2. Mohammad KS, Guise TA. Mechanisms of osteoblastic metastases: role of endothelin-1. Clin Orthop. 2003;415S:S67-S74. 3. Roodman GD. Mechanisms of bone metastases. N Engl J Med. 2004;350:

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 Renal , thyroid Bone mets usually “lead kettle”: Pb KTL … prostate, brst, kidn, thyr, lung Pb = 50/50, as with lung Don’t forget MYELOMA 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 Osteolytic diseases associated with cancer metastases Osteolytic bone metastases are most common in multiple myeloma and breast cancer. Osteolytic bone metastasis is due to an imbalance in the RANKL/OPG ratio. Breast cancer cells secrete factors that increase RANKL level and decrease OPG level; this results in the stimulation of bone resorption. The arrow points to an area of the bone associated with a higher resorption rate or low BMD. Available at: Accessed April 2006.

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 Bone Imaging in Multiple Myeloma Skeletal radiography continues to be the primary diagnostic study to detect destructive bony lesions in multiple myeloma. Four distinct x-ray patterns of involvement have been described: The solitary lesion (plasmacytoma) is typically a lytic lesion primarily involving the spine, pelvis, skull, ribs, sternum, or proximal appendages Diffuse skeletal involvement (myelomatosis) classically manifests as osteolytic lesions with discrete margins and uniform size Diffuse skeletal osteopenia without well-defined lytic lesions is typically seen involving the spine. Multiple compression fractures can be seen as an x-ray manifestation of this condition Sclerosing myeloma lesions are seen in association with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) Magnetic resonance (MR) imaging can provide detailed imaging of the bone and bone marrow Possible MR findings in multiple myeloma include an expansile focal mass, multiple focal masses in the axial skeleton, diffuse marrow involvement, or multiple compression fractures MR is useful in assessing whether spinal compression fractures are due to a focal mass or to the diffuse osteopenia that can result from increased osteolysis in multiple myeloma Computed tomography (CT) scan is a sensitive tool for detecting the bone destructive effects of multiple myeloma CT scan can help define possible lytic or sclerotic lesions CT scan is used to guide biopsy of focal spinal and pelvic lesions Bone scans with technetium-99m rely on an osteoblastic response, which is often absent in multiple myeloma. Bone scan results can underappreciate the extent of bone disease in multiple myeloma and are not useful for screening Angtuaco EJ et al. Radiology. 2004;231:11-23. Reference: Angtuaco EJ , Fassas AB, Walker R, et al. Multiple myeloma: clinical review and diagnostic imaging. Radiology ;231:11-23.

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

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

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) NCCN Practice Guideline-v

34 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

36 Systemic Therapies Pain control Pain medication Radiopharmaceuticals
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 Current options for the management of skeletal morbidity associated with metastatic bone disease Bisphosphonates are effective therapies for the prevention and treatment of skeletal complications due to bone metastases.1-8 Intravenous pamidronate and zoledronic acid are FDA-approved bisphosphonates for the treatment of metastases-induced bone morbidities.9-10 However, there are serious adverse events associated with long-term bisphosphonate therapy. Renal toxicity and osteonecrosis of the jaw are some of the most serious side effects associated with bisphosphonate therapy.11 There is a need for safer and effective therapeutic options for metastases-induced bone diseases. 1. Rosen LS, Gordon D, Kaminski M, et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J. 2001;7: 2. Berenson JR, Lichenstein A, Porter L, et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group. N Engl J Med. 1996;334: 3. Berenson JR, Lipton A. Pharmacology and clinical efficacy of bisphosphonates. Curr Opin Oncol. 1998;10: 4. Hortobagyi GN, Theriault RL, Porter L, et al. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med. 1996;335: 5. Theriault RL, Lipton A, Hortobagyi GN, et al. Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial. Protocol 18 Aredia Breast Cancer Study Group. J Clin Oncol. 1999;17: 6. Hortobagyi GN, Theriault RL, Lipton A, et al. Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. Protocol 19 Aredia Breast Cancer Study Group. J Clin Oncol. 1998;16: 7. Body JJ, Dumon JC, Picart M, Ford J. Intravenous pamidronate in patients with tumor-induced osteolysis: a biochemical dose-response study. J Bone Miner Res. 1995;10: 8. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94: 9. Aredia® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2005. 10. Zometa® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2005. 11. Body JJ, Facon T, Coleman RE, et al. A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clin Cancer Res ;12:

38 Thank You

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