3Clinical Importance and Prognosis of Bone Metastases Disease prevalence, Bone mets. Median U.S. (in thousands) incidence (%) survival (mo)MyelomaRenalMelanomaBladderThyroidLungBreast 1,ProstateNCI, 197; International Myeloma Foundation, 2001.
4Multiple Myeloma Definition B-cell malignancy characterised by abnormal proliferation of plasma cells to produce a monoclonal immunoglobulin ( M protein )
6MM Epidemiology19,900 new cases per yr, 50,000 total cases, 2% cancer deaths in U.S.Higher incidence in African Americans, Pacific IslandersMedian age 71 yrsExposure to radiation, petroleum products, pesticides & Agent OrangeGreenlee RT. CA Cancer J Clin 2001;51:15. Bergsagel DE. Blood 1999;94:1174
7Statistics Second most prevalent blood cancer Approximately 1% of all cancers and 2% of all cancer deaths.45,000 currently have multiple myeloma14,600 new cases of myeloma each year.Responsible for more than 10,000 deaths in the United States annually.
8How 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 cellsProduce antibodies
11What Causes Myeloma Cells To Grow? Adhesion moleculesStromal cellsInteractions:Cytokins (chemical messengers)Growth factors that promote angiogenesisInactivated immune system
12CLINICAL MANIFESTASION Clinical manifestations are related to malignantbehavior of plasma cells and abnormalities produceby M proteinplasma cell proliferation:- multiple osteolytic bone lesions- hypercalcemia- bone marrow suppression ( pancytopenia )monoclonal M protein- decreased level of normal immunoglobulins- hyperviscosity
13Symptoms Anemia Fatigue Bone pain Unexplained bone fractures BackRibsUnexplained bone fracturesRepeated infectionsPneumoniaBladder and kidney infectionUrinary tract infectionWeight lossWeakness and numbness in limbs
14Symptoms Abnormal proteins High level of calcium in blood Blood and urinePolyclonal to Monoclonal proteinsHigh level of calcium in bloodExcessive thirst and urinationSleepinessConstipationNauseaLoss of appetiteMental confusion
15Signs & Symptoms in 1027 Newly Diagnosed Myeloma Patients 1020304050607080BonelesionsFatigueCr >2mg/dLCa >11Wt loss(>9 kg)% patients79Hb<12g/dL73pain6632131912Kyle RA. Mayo Clin Proc 2003;78:21-33
16Screening and Diagnosis Blood and urine testsX-raysMagnetic Resonance Imaging (MRI)Computerized Tomography (CT)Bone marrow examination
17Diagnostic Criteria for Multiple Myeloma Major criteriaI. Plasmacytoma on tissue biopsyII. 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 sampleMinor criteriaa. Bone marrow plasma cells 10-30%b. M spikec. Lytic bone lesionsd. Normal IgM < 50mg, IgA < 100mg, IgG < 600mg/dl
18Diagnostic Criteria for Multiple Myeloma Diagnosis:I + b, I + c, I + dII + b, II + c, II + dIII + a, III + c, I II + da + b + c, a +b + d
19Staging of Multiple Myeloma Clinical stagingis based on level of haemoglobin, serum calcium, immunoglobulins and presence or not of lytic bone lesionssubclassificationA - creatinine < 2mg/dlB - creatinine > 2mg/dl
21Incidence of Chromosomal Abnormalities in MM Genomic AberrationsIncidence of aberrationDel (13)48%Del (17p)11%t(4;14) (p16;q32)14%Hyperdiploidy39%t(11;14) (q13;q32)21%n = 1064 patientsChromosomal changes observed in 90% of patients
22International Staging System (ISS) for Symptomatic Myeloma StageCriteriaMedian Survival (mo)Iβ2m < 3.5 mg/Lalbumin ≥ 3.5 g/dL62II*Not stage I or III44IIIβ2m ≥ 5.5 mg/L29*β2m < 3.5 mg/L and albumin < 3.5 g/dL orβ2m < 5.5 mg/L, any albuminGreipp et al. J Clin Oncol 2005; 23:
23Serum Protein Electrophoresis Monoclonal Protein in MyelomaNormalKyle RA and Rajkumar SV. Cecil Textbook of Medicine, 22nd Edition, 2004
24Distribution 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%
26Normal Bone BiologyBone is always in an active state of remodeling (build up/break down)Resorption: stimulated osteoclasts erode bone, creating a cavityReversal: bone surface is prepared for osteoblasts to begin forming boneFormation: osteoblasts replace resorbed bone and fill the cavity with new boneResting: bone surface rests until a new remodeling cycle beginsAdapted from Novert's Pharmaceuticals
27Vicious cycle of Bone Metastases CORETumor Cells in BoneOsteoblastic factorsEndothelin-1Fibroblast growth factorBone morphogenic proteinsInsulin-like growth factorsBone-derived tumor growth factorsTransforming growth factor Insulin-like growth factorsFibroblast growth factorsPlatelet-derived growth factorBone morphogenic proteinsOsteolytic factorsRANKLPTH-rpInterleukins 1,6,8TNFsM-CSFPathogenesis of Osteoblastic Bone MetastasesSome cancer cells produce soluble paracrine factors (ie, insulin-like growth factor [IGF], fibroblast growth factor [FGF], and bone morphogenic protein [BMP]), causing excessive osteoblast activationProduction 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 growth2,3Osteoblastic metastatic tumor cells release humoral factors, such as PTH-RP and interleukins -6, -8, and -11 that stimulate osteoclastic recruitment and differentiation1Osteoclastic 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 resorptionOsteoblastic activation leads to the release of unidentified osteoblastic growth factors that stimulate tumor cell growth, contributing to the perpetual cycle of abnormal bone formationOf note, in both osteoclastic and osteoblastic bone metastases, osteoclasts are important and make a very likely target for treatmentOsteoblastsOsteoclastsNew boneMineralized bone matrixDerived 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:
28Osteolytic metastases Tumor cells produce growth factors that stimulate bone destructioni.e. RANK ligandOsteoclasts are activated and break down boneOsteoblasts cannot build bone back fast enoughDecreased bone density and strength; high risk for fractureRenal , thyroidBone mets usually “lead kettle”: Pb KTL … prostate, brst, kidn, thyr, lungPb = 50/50, as with lungDon’t forget MYELOMAPatel, B. and DeGroot, H. Orthopedics Journal. 2001;24:612-7.
29Osteoblastic Metastasis Osteoblasts are stimulated by tumors to lay down new boneBone becomes abnormally dense and stiffParadoxically bones are also at risk of breakingOsteolytic diseases associated with cancer metastasesOsteolytic 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.
30Bone Imaging in MMSkeletal radiography is the primary diagnostic test to detect destructive bony lesions in multiple myelomaMRI is useful in assessing whether spinal compression fractures are due to a focal mass or from osteopenia due to increased osteolysisPET scans can be used to detect soft tissue or bone metastasesBone Imaging in Multiple MyelomaSkeletal 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 appendagesDiffuse skeletal involvement (myelomatosis) classically manifests as osteolytic lesions with discrete margins and uniform sizeDiffuse 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 conditionSclerosing 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 marrowPossible MR findings in multiple myeloma include an expansile focal mass, multiple focal masses in the axial skeleton, diffuse marrow involvement, or multiple compression fracturesMR 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 myelomaComputed tomography (CT) scan is a sensitive tool for detecting the bone destructive effects of multiple myelomaCT scan can help define possible lytic or sclerotic lesionsCT scan is used to guide biopsy of focal spinal and pelvic lesionsBone 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 screeningAngtuaco 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.
31Treatment Options Goals: Includes: Attack the cancer Strengthen the boneReduce symptomsIncludes:Systemic therapyLocal therapy
32Clearly not a transplant Can include melphalan- Initial Approach to TreatmentClearly not a transplantcandidatePotential transplantcandidateCan include melphalan-based combinationsNon-alkylator basedinductionStem cell harvest
35Bortezomib (Velcade®) Reversible inhibitor of chymotrypsin-like activity of 26-S proteasomePrevents proteolysis of ubiquitinated proteins & can lead to apoptosis of tumor cellsDosing: 1.3 mg/m2 IV bolus d 1, 4, 8, & 11 (21-d treatment cycle) for a maximum of 8 cyclesFDA approved for MM that has relapsed after ≥1 prior standard therapies
36Systemic Therapies Pain control Pain medication Radiopharmaceuticals Tylenol, NSAIDs (ibuprofen), narcotics, steroidsSuccess can be limited by side effectsRadiopharmaceuticalsStrontium-89 and samarium-153: radioactive particles travel directly to tumor in boneCan reduce pain refractory to other measuresInfrequently used
37Systemic Therapies: Bisphosphonates Bind to and inhibit osteoclast actionInhibit bone breakdownPrevent bone damageImprove bone density and strengthRecommended for almost everyone withcancer bone metastasesCurrent options for the management of skeletal morbidity associated with metastatic bone diseaseBisphosphonates are effective therapies for the prevention and treatment of skeletal complications due to bone metastases.1-8Intravenous pamidronate and zoledronic acid are FDA-approved bisphosphonates for the treatment of metastases-induced bone morbidities.9-10However, 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.11There 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: