Outline. Question 1. Question 2. What is Multiple Myeloma? Andrew Eisenberger, MD

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1 Outline A Disease Overview June 3, 2013 Andrew Eisenberger, MD Assistant Professor of Medicine Hematology/Oncology Columbia Presbyterian Medical Center Introduction Epidemiology/Risk Factors Clinical Features/Diagnostic Evaluation Prognostic Variables Pre malignant conditions: SMM and MGUS Treatment of Multiple Myeloma in 2013 Conclusion Question 1 What of the following patient presentations is NOT compatible with multiple myeloma? a) A 50 year old man with an osteoporotic spine fracture. b) A 66 year old woman with pneumonia and increased total serum protein. c) An asymptomatic 70 year old man with a total WBC of 159,000. d) A 49 year old man with total serum calcium of 16.9 and delirium. e) An 81 year old woman with Hgb 5.6 and dyspnea. Question 2 Mr. P, a 56 year old patient of yours for many years with hypertension and sleep apnea, is admitted with pneumonia. He is noted to be anemic and have an elevated MCV. An astute intern notes that his albumin is 2.9 g/dl and total protein is 4.8 g/dl. A bone marrow biopsy demonstrates 20% monoclonal plasma cells, confirming multiple myeloma. You refer him to a friend who is an oncologist, who starts outpatient multi agent chemotherapy. The patient comes to your office for a visit. He asks for refills for a medication that prevents side effects from his cancer treatment. Question 2 Which of the following medications used to prevent myeloma treatment related side effects might an internist be asked to prescribe? a) Bactrim DS as PCP prophylaxis for once weekly dexamethasone. b) Acyclovir to prevent shingles when taking c) Neupogen to prevent neutropenia when taking d) Gabapentin to prevent peripheral neuropathy when taking lenalidomide (Revlimid). What is Multiple Myeloma? Multiple Myeloma (MM) is a malignant plasma cell malignancy Evolves from two pre malignant conditions: MGUS: Monoclonal Gammopathy of Undetermined Significance Smoldering Myeloma (SMM)

2 How common is MM? Second most common hematologic malignancy Accounting for ~10% of all hematologic malignancies Epidemiology: 61,000 patients in the USA 20,180 patients diagnosed in ,000 patients die of MM each year Treated MM: 5 year OS was 38.2% ( data) 6 month median OS if not treated Ref: SEER Database 2010 Potential Risk Factors Older Age Average age at diagnosis is 70 years Less than 5% of patients are < 45 years Male Gender Ratio 1.7:1 Ethnicity Twice as common in African Americans Environmental?Radiation/Toxins Familial Ref: Introduction to Myeloma, MM Research Foundation Clinical Presentation Signs and Symptoms Bone Pain (60%) Fatigue Wt loss (22%) Paresthesias (5%) Recurrent Infection Renal Failure (20%) Spinal Cord Compression Laboratory Evaluation Elevated total protein high protein gap (Macrocytic) anemia Hypercalcemia Suggested Laboratory Workup CBC with differential Basic Metabolic Panel LDH K/L Serum Free Light Chain Ratio Calcium Quantitative Immunoglobulins Albumin β2 microglobulin Serum Protein Electrophoresis (SPEP) Serum Immunofixation Electrophoresis (SIFE) 24 hour Urine Protein UPEP UIFE Ref: Nau KC, et al. AAFP 2008: October 1 st 78(7): Serum Protein Electrophoresis Serum is exposed to electric current to separate proteins based on size and charge Serum Immunofixation Process by which the monoclonal protein is identified Protein is exposed to antibody against: Light Chains: κ, λ Heavy Chains: G, A, M Complex precipitates and is visible to the naked eye Ref: Images from British Medical Journal, Best Practice Series Ref: Clinical Immunology Reference, University of Pittsburgh Medical Center

3 Urine Studies UPEP and Urine Immunofixation follow the same principles Assay for Bence Jones Proteins Small, monoclonal protein Composed of immunoglobulin light chains only, instead of intact immunoglobulin Radiographic Studies Skeletal Survey Gold Standard MRI If cord compression is suspected PET/CT Not standard of care, but excellent for identifying foci of MM Part of many research protocols Ref: Radiopaedia.org MM teaching file Bone Marrow Biopsy Bone Marrow Plasmacytosis Useful at diagnosis and monitoring of patients with MM High percentage of plasma cells predicts Early Progression Relapse disease Poor OS Plasma Cell Infiltrate Progression Free Overall Survival Survival >15% 15 months (p<0.001) 44 months (p=0.029) 15% 81 months 87 months Ref: Depil S, et al. Leukemia and Lymphoma (2004); 45: Conventional Cytogenetics vs FISH Both are independent prognostic factors at diagnosis Conventional Karyotype identifies abnormalities in 30% of patients FISH can identify chromosomal abnormalities in >90% of MM patients del 13 t(4;14) del(17p) Hyperdiploid chromosomes (extra copy number) Myc Translocation Others

4 Impact on Overall Survival Diagnostic Criteria for MM Presence of M protein in serum or urine Identification of >10% monoclonal plasma cells in bone marrow Evidence of end organ damage: CRAB(I) criteria Calcium Elevation: Ca mg/dl Renal Failure: SCr 2 mg/dl Anemia: Hb < 12 g/dl Bone: lytic lesions, pathologic fracture Infections: Recurrent, due to hypogammaglobulinemia Ref: Avet Loiseau et al. Blood (2007) 109 p Criteria for Smoldering MM Presence of Serum M Protein > 3 g/dl and/or Clonal Plasma cells >10% in the bone marrow Criteria for MGUS Monoclonal Gammopathy of Undetermined Significance No end organ damage that can be attributed to the plasma cell disorder Characterized by serum M protein < 3 g/dl AND Clonal plasma cells <10% in bone marrow Thus, SMM is an asymptomatic condition No end organ damage Also an Asymptomatic Condition Ref: International Myeloma Working Group. Br J Haematol 2003: 121: Epidemiology of MGUS Probability of Progression among 1384 Residents of Southeastern Minnesota in Whom Monoclonal Gammopathy of Undetermined Significance (MGUS) Was Diagnosed from 1960 through 1994 Very Common! 3.2% in Caucasian patients > 50 years old 6 8% in African American patients >50 years old Incidence >10% as patient age increases past 75 Virtually all MM cases are preceded by MGUS Kyle R et al. N Engl J Med 2002;346: Ref: Rajkumar et al. Mayo Clinic Proceedings, 2010 and Kyle RA, et al. NEJM 2002

5 Risk of progression MGUS MM On average, the risk is 1% per year Risk factors for progression: Higher serum M Protein Level > 1.5 g/dl Non IgG MGUS Serum Immunoglobulin Free Light Chain Ratio either <0.26 or >1.65 Risk Risk of Progression at Factors 20 years None 5% One 21% Ref: Rajkumar Blood (2005) Two 37% 106: Three 58% Risk of progression MGUS MM Ref: Rajkumar Blood (2005) 106: Risk of Progression SMM MM Smoldering Myeloma is an intermediate entity between MGUS and active MM Characterized by >10% plasma cells in the bone marrow, and/or by > 3 g/dl M spike However, no end organ damage attributable to the plasma cell dyscrasia Probability of Progression to Active Multiple Myeloma or Primary Amyloidosis in Patients with Smoldering Multiple Myeloma or Monoclonal Gammopathy of Undetermined Significance (MGUS) On average, the risk of developing MM is 10% per year for the first 5 years after diagnosis Kyle R et al. N Engl J Med 2007;356: Ref: Dispenzieri et al, Blood : Staging of Multiple Myeloma Stage International Staging System Median Overall Survival I Serum β2 microglobulin < 3.5 mg/l Serum Albumin 3.5 g/dl 62 months Treatment of Multiple Myeloma II Neither Stage I nor Stage III 44 months Symptomatic or Asymptomatic? Age of patient? Performance status? Goals of Treatment? III Serum β2 5.5 mg/l 29 months Ref: Greipp PR et al. J Clin Oncology 2005; 23:

6 Classes of Myeloma Treatment Should autologous bone marrow transplant be considered in this patient? Cytotoxics Melphalan* Cyclophosphamide Liposomal doxorubicin Immunomodulators Thalodomide Lenalidomide Pomalidomide Proteosome Inhibitors Bortezomib Carfilzomib Corticosteroids Dexamethasone Prednisone Treatment of Multiple Myeloma For transplant eligible patients, the preferred induction regimen is not known Common induction regimens: Lenolidomide (Revlimid) + Dex Bortezomib (Velcade) + Dex CyBorD (Cytoxan, Bortezomib, Dex) RVD (Revlimid, Velcade, Dex) VMP (Velcade, Melphalan, Prednisone)* Bortezomib Based Regimens Given subcutaneously once or twice weekly. Greater toxicity with IV dosing. Side effects: Peripheral neuropathy Thrombocytopenia GI disturbance Zoster reactivation Always ask if your patients are receiving zoster prophylaxis. *Non transplant patients only Thalidomide Introduced as a sedative drug for morning sickness in 1950s in Europe Caused profound limb defects Resurrected in early 1990s when it was studied as a treatment for leprosy Reported by Dr. Bart Barlogie as a treatment for Multiple Myeloma due to its immunomodulatory properties in Lenalidomide Based Regimens Lenalidomide is a derivative of thalidomide Can only be obtained through restricted access program Once daily oral dosing Side effects Cytopenias Deep venous thrombosis Always ask if your patients are receiving aspirin or other antithrombotic.

7 Maintenance Therapy in MM? Since Multiple Myeloma is incurable, even with AutoBMT, there is interest in maintenance strategies to prolong periods of remission. Bortezomib, thalidomide and lenalidomide have all been shown to improve progression free survival after transplant, and sometimes overall survival. Side effects preclude routine use of maintenance. Lenalidomide is associated with an increased risk of second primary malignancies. Question 1 What of the following patient presentations is NOT compatible with multiple myeloma? a) A 50 year old man with an osteoporotic spine fracture. b) A 66 year old woman with pneumonia and decreased total serum protein. c) An asymptomatic 70 year old man with a total WBC of 159,000. d) A 49 year old man with total serum calcium of 16.9 and delirium. e) An 81 year old woman with Hgb 5.6 and dyspnea. Question 2 Which of the following medications used to prevent myeloma treatment related side effects might an internist be asked to prescribe? a) Bactrim DS as PCP prophylaxis for once weekly dexamethasone. b) Acyclovir to prevent shingles when taking c) Neupogen to prevent neutropenia when taking d) Gabapentin to prevent peripheral neuropathy when taking lenalidomide (Revlimid). Conclusions New treatments have improved the outlook for patients with MM Still, the curve has yet to plateau and Myeloma remains incurable More research/ better treatments are needed Ref: Kumar SK, Blood 2008; 111: