1. Elizabeth Bilotti, MSN, RN, APN-BC Nurse Practitioner Multiple Myeloma Division John Theurer Cancer Center at HUMC Hackensack, New Jersey Clinical Management of Skeletal Integrity in Multiple Myeloma: The Role of the Oncology Nurse in Optimizing Patient Outcomes This program is supported by an educational donation from

2. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Overview  Multiple myeloma and associated bone complications  Mechanisms of bone destruction  Current and emerging treatment interventions  Adverse events associated with treatments  Nursing interventions

3. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Multiple Myeloma: Normal vs Abnormal Plasma Cells  Cancer of the plasma cells in bone marrow  Growth of myeloma cells –Disrupts normal bone marrow function –Reduces normal immune function –Results in abnormal production and release of monoclonal protein into blood and/or urine –Destroys and invades surrounding bone Healthy Multiple Myeloma B cell Antigens Plasma cell Genetic damage Multiple myeloma cell Damaged B cell Bone Marrow Barlogie B, et al. In: Williams Hematology. 7th ed. 2006:1501.

4. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma  Second most common hematologic malignancy in US [1]  Incidence rises with age and is more prevalent at 65 years of age or older [1]  Incidence in blacks is 2 times that of whites [2]  5-yr survival rate is ~ 37% (higher in younger patients) [3] 1. Singhal S, et al. Clin J Am Soc Nephrol. 2006;1:1322-1330. 2. American Cancer Society. Available at: http://www.cancer.org/acs/groups/content/@nho/documents/document/cffaa20092010pdf.pdf. 3. American Cancer Society. Available at: http://www.cancer.org. Multiple Myeloma Prevalence and Statistics FemaleMaleBoth sexes 25,000 20,000 15,000 10,000 5000 0 New CasesDeaths

5. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Disease Staging Durie Salmon Staging StageCriteriaMyeloma Cell Mass 2 (cells x 10 12 /m 2 ) IAll of the following: Hb > 10, calcium ≤ 12, normal bone or solitary plasmacytoma Low M-component: IgG < 5 g/dL, IgA < 3 g/dL, UPEP < 4 g/24 h < 0.6 IINeither fitting I or III0.6-1.20 III1 or more of the following: Hb 12, advanced lytic bone disease High M-component: IgG > 7 g/dL, IgA > 5 g/dL, UPEP > 12 g/24 h > 1.20 ISS Staging StageCriteria ISerum β 2 -microglobulin < 3.5 mg/L Serum albumin ≥ 3.5 g/dL IINot stage I or stage III IIISerum β 2 -microglobulin ≥ 5.5 mg/L 1. NCCN. Available at: http://www.nccn.org. 2. Durie BG, et al. Cancer. 1975;36:842-854. 3. Greipp PR, et al. J Clin Oncol. 2005;23:3412-3420. Subclassification: A: Serum creatinine < 2 mg/dL B: Serum creatinine ≥ 2 mg/dL

6. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Prognostic Significance of Bone Findings and Staging  MRI –Single lesions on x-ray with additional lesions identified on MRI have a shorter TTP and time to starting therapy than those with normal MRI findings [1] –Patients with advanced disease and normal MRI findings have longer survival than those with diffuse or focal MRI findings [1] –Resolution of focal lesions on MRI posttreatment predicts for superior survival [1]  PET/CT –Number of FDG-avid focal lesions was positively linked to high B 2 -microglobulin, C-reactive protein and LDH [2] –≥ 3 FDG-avid focal lesions was the leading independent parameter associated with inferior OS and EFS [2] StageOriginal Durie/ Salmon Durie/ Salmon Plus StageISS Median Survival, Mos IABAB 69 22 72 20 I62 IIABAB 58 34 61 28 II44 IIIABAB 45 24 40 19 III29 1. Dimopoulos M, et al. Leukemia. 2009:1-12. 2. Bartel TB, et al. Blood. 2009;114:2068-2076. Subclassification: A: Serum creatinine < 2 mg/dL B: Serum creatinine ≥ 2 mg/dL

7. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Scope of the Problem  ~ 80% of patients with multiple myeloma will have evidence of skeletal involvement on skeletal survey –Vertebrae: 65% –Ribs: 45% –Skull: 40% –Shoulders: 40% –Pelvis: 30% –Long bones: 25% Dimopoulos M, et al. Leukemia. 2009:1-12.

8. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Consequence of Bone Loss  Severe bone pain  Fractures  Spinal cord compression  Limited mobility  Hypercalcemia  Decrease in quality of life Gralow JR, et al. J Natl Compr Canc Netw. 2009;7(suppl 3):S1-S32.

9. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Bone Remodeling  Continuous throughout life  Osteoblasts: cells that create bone  Osteoclasts: cells that break down bone  Osteoblastic and osteoclastic activity is tightly coupled and balanced –Resorption = growth  Ensures skeletal integrity  Maintains mineral homeostasis

10. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Pathogenesis of Osteolytic Bone Metastases  Tumor-derived osteoclast activating factors –Parathyroid hormone- related protein –Interleukin-6, -8, -11 –Tumor necrosis factor –Macrophage colony- stimulating factor  Bone-derived tumor growth factors –Transforming growth factor  –Insulin-like growth factors –Fibroblast growth factors –Platelet-derived growth factor –Bone morphogenic proteins Bone Tumor Cells in Bone Osteoclast (+) Derived from Roodman GD. N Engl J Med. 2004;350:1655-1664.

11. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Clinical Manifestations of Multiple Myeloma Renal compromise (30%) [1] M protein Bone pain (~ 60%) [3] Neuropathy (~ 80%) [2] Hypercalcemia (~ 15%) [3] Immune deficiency Anemia (~ 70%) [3] Lytic lesions (~ 70%) [3] Infection (15%) Marrow infiltration Destruction of bone 1. Chanan-Khan AA, et al. Blood. 2007;109:2604-2606. 2. Richardson PG, et al. J Clin Oncol. 2006;24:3113-3120. 3. Kyle RA, et al. Mayo Clin Proc. 2003;78:21-33

12. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Myeloma Disease Classifications NameDefinition MGUS  Monoclonal protein present (BMBx < 10% plasma cells)  No underlying disease state  Monitor (over time, risk of progression to MM or related disorder up to 30% or 1%/yr) Asymptomatic myeloma  Higher level of disease than MGUS but still no symptoms or organ damage (BMBx > 10% plasma cells)  Monitor Symptomatic myeloma  Monoclonal protein (BMBx > 10% plasma cells) and ≥ 1 CRAB features of organ damage present  Begin treatment International Myeloma Working Group. Br J Haematol. 2003;121:749-757.

13. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Diagnostic Criteria for Symptomatic Multiple Myeloma  Monoclonal plasma cells in bone marrow (≥ 10%)  M protein in serum and/or urine  ≥ 1 CRAB features of organ damage C: calcium elevation (> 11.5 mg/L or ULN) R: renal dysfunction (serum creatinine > 2 mg/dL) A: anemia (Hb < 10 g/dL or 2 g < normal) B: bone disease (lytic lesions or osteoporosis) NCCN. Available at: http://www.nccn.org.

14. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Mechanism of Bisphosphonate Inhibition of Osteoclast Activity Bisphosphonates inhibit osteoclast activity, and promote osteoclast apoptosis [1] Bisphosphonates are released locally during bone resorption [1] Bisphosphonates are concentrated under osteoclasts [1] Bisphosphonates may modulate signaling from osteoblasts to osteoclasts New bone X Bone  Increased OPG production [2]  Decreased RANKL expression [3] 1. Reszka AA, et al. Curr Rheumatol Rep. 2003;5:65-74. 2. Viereck V, et al. Biochem Biophys Res Commun. 2002;291:680-686. 3. Pan B, et al. J Bone Miner Res. 2004;19:147-154.

15. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Comparison of Dosing Recommendations ASCO  Monthly bisphosphonate for 2 yrs [1]  After 2 yrs [1] –Consider stopping with responsive or stable disease [1] –Further use at clinician discretion [1] –Resume treatment at relapse with new onset skeletal events [1]  Adequate dental hygiene [1] IMWG  Monthly bisphosphonate for 1 yr [2]  After 1 yr [2] –D/C if CR or VGPR occurs without evident active bone disease [2] –Continue if < VGPR or active bone disease evident [2]  After 2 yrs [2] –D/C if no active bone disease present [2] –If active bone disease is present, further use is at the clinicians discretion [2]  Need for adequate dental evaluation [2] 1. Kyle R, et al. J Clin Oncol. 2007;25:2464-2472. 2. Durie BG, et al. Mayo Clin Proc. 2007;81:1051-1053.

16. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Recommended Doses and Infusion Times DrugDose/Infusion TimeInterval Estimated CrCl > 60 mL/min Pamidronate Zoledronic acid 90 mg over 2-3 hrs 4 mg over 15 mins 3-4 wks Estimated CrCl 30 to < 60 mL/min Pamidronate Zoledronic acid 90 mg over 2-3 hrs* Reduced dosage † 3-4 wks Estimated CrCl < 30 mL/min Pamidronate Zoledronic acid 90 mg over 4-6 hrs* Not recommended 3-4 wks *Consider dose reduction. † 3.5mg (CrCl 50-60 mL/min); 3.3 mg (CrCl 40-49 mL/min); 3.0 mg (CrCl 30-39 mL/min). Kyle R, et al. J Clin Oncol. 2007;25:2464-2472.

17. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Balloon Kyphoplasty: Treatment for Tumor-Related VCFs Stabilizes the fracture and corrects spinal deformity caused by VCFs Bouza C, et al. BMC Palliat Care. 2009;8:12.

18. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Evaluations That Should Occur Prior to Bisphosphonate Support  Education regarding potential adverse effects  Dental evaluation –Biannual exams recommended –Minimize periodontal inflammation –Treat active oral infection –Provide routine restorative care for carious teeth and endodontic care for unsalvageable teeth

19. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma IV Bisphosphonates: Adverse Effects  Bone pain [1] –Avoid NSAID use in MM patients for management  Nausea (minor) [1]  Flulike symptoms (acute phase response) [1]  Anemia [2]  ONJ [1]  Hypocalcemia [1] –Consider supplementation with calcium and vitamin D at the clinician discretion 1. Papapetrou PD. Hormones (Athens). 2009;8:96-110. 2. Wellington K, et al. Drugs. 2003;63:417-437.

20. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Bisphosphonates and Osteonecrosis  Uncommon complication causing avascular necrosis of maxilla or mandible  Suspect with tooth or jaw pain or exposed bone  May be related to duration of therapy  True incidence unknown Papapetrou PD. Hormones (Athens). 2009;8:96-110.

21. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Bisphosphonates and ONJ  Meta-analysis performed in 2006 [1] –368 reported cases –94% of patients were treated with IV bisphosphonates, and 85% had MM or breast cancer  Sites of involvement [1] –Mandible only (65%), maxilla only (26%), both (9%) –Most lesions noted on posterior lingual mandible near the mylohyoid ridge  60% of cases occurred after tooth extraction or other dentoalveolar surgery, remaining occurred spontaneously (often in those wearing dentures) [1] –39% of spontaneous cases occurred on bony exostoses that were easily traumatized  International Myeloma Foundation Web survey [2] –4.0% of 904 respondents reported ONJ with pamidronate, 10.0% with zoledronic acid, and 6.8% reported suspicious lesions 1. Woo SB, et al. Ann Intern Med. 2006;144:753-761. 2. Durie BG, et al. N Engl J Med. 2005;353:99-102.

22. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Recommended Interventions for Management of ONJ Patient CategoryTreatment Recommendations Group 1: patients about to begin amino- bisphosphonate therapy  Treat active oral infections, eliminate sites at high risk for infection (partially impacted wisdom teeth, nonrestorable teeth, or teeth with substantial periodontal bone loss)  Encourage routine dental care Group 2: patients without ONJ who are receiving IV aminobisphosphonate therapy Fewer than 3 mos of drug therapy  Same as above for group 1 Longer than 3 mos of drug therapy  Seek conservative alternatives to surgical procedures with appropriate local and systemic antibiotics  Perform extractions and other surgery using minimal bone manipulation with appropriate local and systemic antibiotics; follow up to ensure healing Group 3: patients with ONJSame as above for group 2 with more than 3 mos of drug therapy Consider additional imaging studies, such as CT scans Perform conservative removal of dead bone as necessary with minimal trauma to adjacent hard and soft tissues Prescribe oral rinses, prescribe systemic antibiotic therapy, prescribe systemic analgesics as indicated, prescribe a soft acrylic stent Suggest discontinuation of bisphosphonate therapy until osteonecrosis heals or underlying disease progresses Woo SB, et al. Ann Intern Med. 2006;144:753-761.

23. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Imaging Techniques Type of ImagingFindingsRecommended Use Conventional radiography (x-rays) Lytic lesions Diffuse osteoporosis At the time of diagnosis (used for Durie-Salmon staging) Further imaging needed during follow-up CTLytic lesions (too small to detect on x- ray) Evaluate extent of associated soft tissue masses Superior to x-ray at estimating fracture risk and instability Useful for evaluating patients that are symptomatic despite having no evidence of osteolysis on skeletal survey MRIDegree of MM cell infiltration before bone destruction visible on x-ray (focal disease vs diffuse infiltration) Differentiate between benign and malignant coimpression fracture Amyloid deposition (soft tissue and cardiac) Evaluate for cord compression Determine % loss of vertebral height prior to vertebroplasty and kyphoplasty Evaluate for AVN PET/CTPersistent or recurrent osseous disease Localizing extramedullary sites of disease Monitor patients with nonsecretory myeloma Evaluate for other areas of involvement in patients with suspected solitary plasmacytoma Dimopoulos M et al. Leukemia. 2009:1-12.

24. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Renal Toxicity From Bisphosphonates Pamidronate  Collapsing or noncollapsing focal segmental glomerulosclerosis or minimal change disease –Glomerular damage –Nephrotic syndrome (> 3.5 g/day) –Renal insufficiency Zoledronic acid  Acute tubular necrosis –Tubular damage –Subnephrotic proteinuria –Acute kidney injury Dose dependant Infusion time dependant Perazella MA, et al. Kidney Int. 2008;74:1385-1393.

25. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Managing Renal Safety  Normal baseline serum creatinine (< 1.4 mg/dL) –Withhold temporarily if serum creatinine increases ≥ 0.5 mg/dL  Abnormal baseline serum creatinine (≥ 1.4 mg/dL) –Withhold temporarily if serum creatinine increases ≥ 1.0 mg/dL  Can resume therapy once serum creatinine returns to within 10% of baseline Zoledronic acid [package insert].

26. Nursing Considerations

27. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Talking With Multiple Myeloma Patients  Disease is incurable but treatable  Goals of therapy include –Restore and maintain skeletal integrity –Reduce or palliate pain –Manage or preserve kidney function –Manage cytopenias –Maintain maximal quality of life (wellness)

28. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Planning Bone Healthcare  Assessing need and setting goals –Enhance quality of life –Maintain maximum bone health –Prevent complicating factors –Be prepared for future challenges  Implementation and evaluation –Develop an index of suspicion to facilitate early intervention –Prepare caregivers to manage chronic care issues –Educate, reassure, and support

29. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Understand the Patient and Family First  How do the patients define quality of life?  What is important to them?  What resources do they have/need?  What do they understand?  Treat the cause if at all possible  Prevent immobilization  Supportive/restorative care

30. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Interventions for Maintaining Bone Health  Therapeutic  Pharmacologic  Exercise –Weight-bearing exercise facilitates normal remodeling –Keeping it simple enhances compliance; walk!  Physician advice is important for patients with health issues  Maintain a healthy lifestyle –Don’t smoke –No more than 2-3 ounces of alcohol daily  Diet –Moderate protein intake –Limited sodium (salt) intake –Calcium and vitamin D are essential for building bone

31. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Continued Improvement in 5-Yr OS in Multiple Myeloma SEER Cancer Fast Stats. Available at: http://seer.cancer.gov/faststats/selections.php?#Output. 5-Yr Relative Survival by Yr Dx by Cancer Site All Ages, All Races, Both Sexes 1975-2002 Myeloma Cancer sites include invasive cases only unless otherwise noted. Survival source: SEER 9 areas (San Francisco, Connecticut, Detroit, Hawaii, Iowa, New Mexibo, Seattle, Utah, and Atlanta). The 5-yr survival estimates are calculated using monthly intervals. Yr of Diagnosis 1975198019851990199520002002 Percentage 0 5 10 15 20 25 30 35 40 45

32. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Biomarkers of Multiple Myeloma  Several biomarkers identified by pharmacogenomic research –Receptor activator of NF-kB ligand [1] : marker of cytokine stimulation and cell adhesion –Macrophage inflammatory protein 1-alpha [2] –Tumor necrosis factor [3] –B lymphocytes stimulator [4] : marker of survival and proliferation 1. Terpos E, et al. Blood. 2003;102:1064-1069. 2. Roussou M, et al. Leukemia. 2009;23:2177-2181. 3. Hideshima T, et al. Oncogene. 2001;20:4519-4527. 4. Jiang P, et al. Eur J Haematol. 2009;82:267-276.

33. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma New Agents Under Investigation 1. Vij R, et al. Am J Hematol. 2009;84:650-656. 2. Heider U, et al. Biochem Biophys Res Commun. 2005;338:687-693. 3. Gavriatopoulou M, et al. Expert Opin Ther Targerts. 2009;13:839-848.  Denosumab –Phase II single-arm study of denosumab in 46 patients with relapsed or plateau- phase MM [1] –Median decreases of 70% and 52% reported for relapsed and plateau-phase patients, respectively [1]  DKK1 inhibition –DKK1 is secreted by MM cells [2] –Reduces osteoblast differentiation [3] –Inhibition in animal models led to [3] –Increased numbers of osteoblasts [3] –Reduced numbers of multinucleated osteoclasts [3] –Increased bone volume [3] –Associated with reduced myeloma burden [3]

34. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Denosumab in MM Patients With Lytic Bone Disease  Double-blind, double-dummy phase I trial  Single dose of –Denosumab SC at 0.1, 0.3, 1.0, or 3.0 mg/kg or –Pamidronate IV 90 mg  Assess markers of bone resorption –Urine and serum N-telopeptide levels lasted for 84 days following dose Body JJ, et al. Clin Cancer Res. 2006;12:1221-1228.

35. clinicaloptions.com/oncology Bone Disease in Multiple Myeloma Potential Benefits of New Antimyeloma Drugs on Myeloma Bone Disease  Bortezomib, thalidomide, and arsenic trioxide are NF-kB inhibitors [1,2] –Block RANK signaling –Inhibit osteoclast function  Bortezomib –Increases bone formation marker, bone alkaline phosphatase in responding patients [3,4] –Stimulates osteoblast function [5] –Increases BMP production –Blocks DKK1 expression –Bone resorption markers suppressed in responding patients 1. Ma MH, et al. Clin Cancer Res. 2003;9:1136-1144. 2. Li ZW, et al. Curr Opin Hem. 2008;15:391-399. 3. Zangari M, et al. Br J Haematol. 2005;131:71-73. 4. Shimazaki C, et al. Leukemia. 2005;19:1102-1103. 5. Oyajobi. BO, et al. Br J Haematol. 2007;139:434-438.

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