1. The Importance of Survivorship in Multiple Myeloma Beth Faiman MSN, APRN, BC, AOCN® Nurse Practitioner, Taussig Cancer Institute, Cleveland Clinic Pre-Doctoral Research Fellow, Francis Payne Bolton School of Nursing at Case Western Reserve Cleveland, Ohio Mail to: faimanb@ccf.orgfaimanb@ccf.org

2. Multiple Myeloma A cancer of bone marrow plasma cells Incurable but very treatable Side effects of treatment are manageable Newer agents offer hope of improved survival in the last decade –SEER data—5-year OS 26%  33% Faiman, B. (2010). Treatment modalities: Newly Diagnosed, Non-transplant Eligible. Jemal, A., R. Siegel, et al. (2009). "Cancer statistics, 2009." CA A Cancer Journal for Clinicians 56(2): 106-130.

3. Immunoglobulin Structure and Dysfunction Immunoglobulins: Integral to immune system function Dysfunction of Heavy and light chains Heavy: IgG, IgA, IgD and IgE Light: Kappa, Lambda Serum Kappa/Lambda Free Light Chains Non-secretory MM Noonan, K. (2010). Anatomy and Physiology Multiple Myeloma: A Textbook for Nurses J. D. Tariman. Pittsburgh, ONS Publishing 9-25. Open access artwork used under the terms of the GNU free documentation license http://commons.wikimedia.org/wiki/File:Immunoglobulin_basic_unit.svghttp://en.wikipedia.org/wiki/GNU_Free_Documentation_License

4. Diagnostic Tests Blood and Urine Tests –Generic blood analysis Complete blood cell counts (CBC) Calcium, uric acid and creatinine Albumin, Beta-2-microglobulin, LDH –M proteins Blood—Serum protein electrophoresis and Immunofixation Urine protein electrophoresis and immunofixation Quantitative Immunoglobulins, serum free light chain assay Radiologic Skeletal survey; MRI/computerized tomography (CT) scanning or PET if needed Bone Marrow Aspirate and biopsy with karyotyping and plasma cell labeling index NCCN 2010 Multiple Myeloma Clinical Practice Guidelines in Oncology. The Complete Library of NCCN Clinical Practice Guidelines in Oncology [CD-ROM]. Jenkintown, PA: Author.

5. Criteria for Diagnosis of MM Monoclonal plasma cells in bone marrow (  10%/  30% if non-secretory) Monoclonal protein present in serum and/or urine Myeloma-related organ dysfunction –Calcium  in serum (>10.5 mg/L) –Renal insufficiency (SCr >2 mg/dL) –Anemia (hemoglobin <10 g/dL or 2g <normal) –Bone lesions or osteoporosis Durie, B. G., R. A. Kyle, et al. (2003). "Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation." Hematol J 4(6): 379-398 Kyle, R. A. and S. V. Rajkumar (2008). "Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma." Leukemia 23(1): 3-9.

6. Kaplan-Meier Curve for Myeloma patients 1975-2004

7. Myeloma Survivorship: Average Years of Life Lost in Patients Treated With Conventional or High-Dose Therapy Adapted from : Ludwig, H., V. Bolejack, et al. (2010). "Survival and Years of Life Lost in Different Age Cohorts of Patients With Multiple Myeloma." J Clin Oncol 28(9): 1599-1605. Treatment<4040-4950-5960-6970-79 Conventional chemo #pts1238051,2592,8091,709 Mean expected survival yrs 42.733.125.717.611.5 Avg yrs life lost36.827.421.013.68.1 High dose chemo #pts1895721,96279435 Mean expected survival yrs 42.233.62519.312.7 Avg yrs life lost35.925.618.213.110.6 Age at Diagnosis

8. Teaching slide provided by Blood found in: Kumar, S. K., S. V. Rajkumar, et al. (2008). "Improved survival in multiple myeloma and the impact of novel therapies." Blood 111(5): 2516-2520. Impact of Novel Agents: Overall survival from diagnosis of MM

9. Teaching slide provided by Blood. Found in: Ludwig, H., B. G. M. Durie, et al. (2008). "Myeloma in patients younger than age 50 years presents with more favorable features and shows better survival: an analysis of 10 549 patients from the International Myeloma Working Group." Blood 111(8): 4039-4047. Cumulative relative survival in patients treated with conventional therapy (A) and high-dose therapy (B) in patients younger than 50 years or 50 years and older and in patients younger than 40 years or 40 years and older (C,D)

10. What to look for… Unexpected long term complications Second cancers (alkylating agents) Maintenance vs. No maintenance Sexuality issues Family/Social problems Financial/Insurance concerns Other

11. Thalidomide (Thalomid ® ) FDA approved for newly diagnosed and relapsed MM Patients who receive thalidomide had improved survival over patients receiving steroids in clinical trials When given to patients after transplant, thalidomide has been shown to improve survival and extend remission Celgene Corporation (2007). "Thalomid (Thalidomide) package insert. Summit, NJ: Author. Rajkumar, S. V., E. Blood, et al. (2004). "A randomized phase II trial of thalidomide plus dexamethasone versus dexamethasone in newly diagnosed multiple myeloma (E1A00): A trial coordinated by the Eastern Cooperative Group [Abstract # 6508]." Proceedings of the American Society of Clinical Oncology 22: 560s. Attal, M., J.-L. Harousseau, et al. (2006). "Maintenance therapy with thalidomide improves survival in patients with multiple myeloma." Blood 108(10): 3289-3294.

12. Side Effects of Thalidomide Common –Birth defects –peripheral neuropathy –Somnolence, Fatigue –Rash –Constipation –DVT (common in combination with Dex or other agents) Less Common –Stevens-Johnson syndrome (adverse reaction to drugs) –Elevated liver enzymes –Malaise –Peripheral edema Celgene Corporation (2007). "Thalomid (Thalidomide) package insert. Summit, NJ: Author."

13. Bortezomib (Velcade ® ) FDA approved for newly diagnosed and relapsed MM Has been shown to improve survival in elderly patients with newly diagnosed MM compared to dex, MP or VMP Extends remissions in patients with relapsed MM San Miguel, J. F., R. Schlag, et al. (2008). "Bortezomib plus Melphalan and Prednisone for Initial Treatment of Multiple Myeloma." N Engl J Med 359(9): 906-917. Richardson, P., B. Barlogie, et al. (2003). "A phase 2 study of bortezomib in relapsed, refractory myeloma." N Engl J Med 348: 2609-2617.

14. Frequent Side Effects of Bortezomib Thrombocytopenia Asthenia –Fatigue, weakness GI effects –Nausea, vomiting, diarrhea Peripheral neuropathy Hypotension Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc; 2007.

15. Lenalidomide (Revlimid ® ) FDA approved for relapsed MM Clinical trials have demonstrated improved remission rates in combination with dexamethasone and bortezomib Will extend progression free survival in elderly patients when len is given after MPR Extends remission after transplant Weber, D. M., C. Chen, et al. (2007). "Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America." N Engl J Med 357(21): 2133-2142. Richardson, P., E. Weller, et al. (2010). "Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma." Blood Attal, M., C. Cristini, et al. (2010). "Lenalidomide maintenance after transplantation for myeloma." J Clin Oncol (Meeting Abstracts) 28(15_suppl): 8018

16. Lenalidomide Only available through restricted distribution program “RevAssist SM ” because of potential for human birth defects. Different toxicity profile than thalidomide –Greater myelosuppression –Fatigue, Asthenia –Renally excreted –GI Revlimid ® (lenalidomide) prescribing information. Available at: http://www.celgene.com/PDF/RevlimidPI.pdf

17. Bone Health: Scope of Problem Over 58% of patients have back and bone pain at diagnosis 15%-30% develop VCFs annually leads to altered biomechanics and increases risk of health problems About half of patients with at least 1 osteolytic lesion develop pathologic fractures within 9 months Patients at risk for pain, hypercalcemia, decreased mobility and spontaneous fractures if MM not controlled Kyle, R. A. and S. V. Rajkumar (2004). "Multiple myeloma." N Engl J Med 351(18): 1860-1873. Roodman, G. D. (2008). "Skeletal Imaging and Management of Bone Disease." Hematology 2008(1): 313-319.

18. Pathobiology of Bone Disease Pathobiology: malignant cells produce osteoclast- activating factors that destroy bone cells –Osteoclast stimulation leads to extensive osteolysis, severe bone pain, and pathologic fractures –Spinal cord compression Skeletal survey, MRI, CT, PET to diagnose Treatment: Analgesia, bisphosphonaes, treat disease if relapse, vertebroplasty or balloon kyphoplasty Roodman, G. D. (2008). "Skeletal Imaging and Management of Bone Disease." Hematology 2008(1): 313-319.

19. Interventions for Bone Disease Patients with bone disease are at risk of increased morbidity and mortality –VTE, Pneumonia Quality of life Vertebraplasty vs Balloon Kyphoplasty Radiation for identified lesions Physical therapy to increase function, mobility Bisphosphonates, Ca++, Vit D Roodman, G. D. (2008). "Skeletal Imaging and Management of Bone Disease." Hematology 2008(1): 313-319.

20. Kidney Dysfunction Bence-Jones proteinuria/Free monoclonal light Chains: Incidence ~70% Light chain Igs can precipitate and damage renal cells Free light chains filtered in the nephron’s glomerulus, then absorbed and metabolized by proximal tubular cells Heavy and light chains can cause renal tubular damage Serum Free light chain assay more reliable than urine –ATN secondary to NSAID use, dehydration, nephrotoxic agents (CT dyes) –Supportive therapy Hydration, correct underlying cause with treatment Avoid IV contrast and nephrotoxic agents (IV dyes, NSAIDS, aminoglycosides especially) Plasmapheresis, dialysis Durie, B. G., R. A. Kyle, et al. (2003). "Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation." Hematol J 4(6): 379-398. Chanan-Khan, A. A., J. L. Kaufman, et al. (2007). "Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: a multicenter retrospective study." Blood 109(6): 2604-2606.

21. Conclusions Patients with MM are living longer than ever! Nurses are in a unique position to educate patients, assess for side effects, and intervene when appropriate New and unidentified survivorship issues may become apparent with increased lifespan