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METHOD OF PARTICIPATION

METHOD OF PARTICIPATION. Prior to the start of the program, please check your syllabus to ensure you have the following printed program materials: Pre-activity Survey Located at the front of your syllabus CME Evaluation with Post-activity Survey Located at the back of your syllabus.

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METHOD OF PARTICIPATION

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  1. METHOD OF PARTICIPATION • Prior to the start of the program, please check your syllabus to ensure you have the following printed program materials: • Pre-activity Survey • Located at the front of your syllabus • CME Evaluation with Post-activity Survey • Located at the back of your syllabus

  2. Disclosures All relevant financial relationships with commercial interests reported by faculty speakers, steering committee members, non-faculty content contributors and/or reviewers,or their spouses/partners have been listed on page 5 of your program syllabus. Off-label Discussion Disclosure This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.

  3. Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: • Assess the prognosis of patients based on risk stratification and patient- and disease-related characteristics that influence the selection of optimal treatment in frontline, maintenance, and relapsed/ refractory settings • Review current and emerging maintenance therapy options considered for MM • Review treatment options for patients with relapsed/refractory MM • Identify and manage common treatment-related toxicities in MM • Evaluate clinical trial opportunities for patients with relapsed/refractory MM

  4. Pre-activity Survey • Please remove the Pre-activity Survey from the front of your packet • Your answers are vital to our understanding of the effectiveness of this CME/CE program, and will help shape future educational activities and topics • Please fill in the most appropriate answer(s) for the questions below: • Degree:  MD/DO Nursing Professional PharmD Other: _____________________________ • Specialty: Oncology/Hematology  Transplant specialist  Internal Medicine Other: ___________

  5. Pre-activity Survey Question 1 Please rate your current level of confidence in treating and managing patients with MM: 1 2 3 4 5 Not knowledgeable Expert

  6. Pre-activity Survey Question 2 Please rate your current level of competence in using emerging data from clinical studies to individualize treatment options for patients with MM: 1 2 3 4 5 Not competent Expert

  7. Pre-program Survey Question 3 A 52-year-old patient presents with asymptomatic anemia of 10g/dL and total serum protein 10 g/L. The workup reveals multiple lytic lesions, an IgA kappa peak of 3.2, cytogenetic t4:14, 30% plasma cells, and Beta 2 microglobulin of 5.0. Which of the following options best describes the patient’s risk stratification and suitable induction therapy? • Low-risk; bortezomib + dexamethasone • High-risk; lenalidomide + bortezomib + dexamethasone • High-risk; thalidomide + melphalan + prednisone • Low-risk; thalidomide + dexamethasone

  8. Pre-program Survey Question 4 Which of the following is not a supportive care consideration that you would discuss with your patient being treated with a lenalidomide + dexamethasone regimen? • There is a very high risk of peripheral neuropathy with this regimen • Prophylactic treatment for deep vein thrombosis should be initiated • Anticipate the possibility of infection • There are long-term complications, such as diarrhea and fatigue

  9. Pre-program Survey Question 5 An 80-year-old male is diagnosed with MM. The work-up revealed 3 compression fractures, 60% kappa plasma cells in the bone marrow, normal calcium levels, hyperdiploidy on FISH, and comorbidities include diabetes, hypertension, obesity, and atrial fibrillation. He relapses after frontline lenalidomide + dexamethasone and second-line CyBorD. Relapse occurred 42 days after completion of CyBorD. What treatment option would you now consider for this patient? • Carfilzomib • Pomalidomide • Clinical trial • All of the above

  10. Pre-program Survey Question 6 Which of the following agents is not recommended by NCCN as maintenance therapy for multiple myeloma? • Lenalidomide • Pomalidomide • Thalidomide • Bortezomib • None of the above

  11. Multiple Myeloma: Epidemiology • Approximately 22,400 new cases in 2013 • 10,800 associated deaths • African Americans >2x • Hispanics 1.7x • Median age 66 years • Age <50 years: 10% • Age <40 years: 2% Cancer Facts and Figures. American Cancer Society. 2013.

  12. Progression of the Disease MGUS Smoldering MM Active MM Extramedullary MM Cell line Clonal cells >10% End organ damage BM independence Kuehl WM, Bergsagel PL. Nat Rev Cancer. 2002;2:175-187.

  13. CLINICAL CRITERIA Evidence of plasma cell clone Usually >10%, but not always LABORATORY TESTING Diagnosis of Myeloma • Any level of protein • Difference between SMM and MM is CRAB “M spike” Polyclonal hump Alb a1 a2 b g Alb. a1 a2 b g Polyclonal protein Monoclonal protein Picture courtesy of Drs. R. Kyle and J. Katzmann. Mayo Clinic; NCCN Clinical Practice Guidelines v2.2013.

  14. Importance of Progression Events CRAB CRITERIA • Calcium elevation • Renal disease • Anemia • Bone disease C A R B DurieBG et al. Leukemia. 2006;20:1467-1473.

  15. Multiple Myeloma: Prognosis • Survival statistics unknown now • If not high risk, many survive 10 years • High risk = 3 years • Some 10%-20% of patients have long-term control with SCT • Prognosis dictated by host features and genetics • High risk – 17p13, t(4;14), and t(14;16) • Gene expression profiling • Other markers: high LDH, hypodiploidy, IgA, plasmablastic • International Staging System (ISS) is useful to compare trials, not individually • ISS has replaced the Durie-Salmon staging system Fonseca R et al. Leukemia. 2009;23:2210-2221.

  16. Case Discussions

  17. Myeloma Tales of Two Cases Case 1 Case 2 55-year-old female presents with asymptomatic anemia of 10 g/dL and total serum protein 10 g/L Work-up reveals 30% plasma cells Cytogenetic t 4,14 IgA kappa peak of 3.2 Beta 2 microglobulin of 5.0 Survey multiple lytic lesions What induction therapy should she receive? • 55-year-old female presents with asymptomatic anemia of 10 g/dL and total serum protein 10 g/L • Work-up reveals • 30% plasma cells • Cytogenetic diploid • IgA kappa peak of 3.2 • Beta 2 microglobulin of 3.0/Albumin 2.0 g/dL • Survey no lytic lesions • What induction therapy should she receive?

  18. Q1. What is the preferred treatment regimen for Patient #1 & #2 at this point? • Thalidomide + dexamethasone (TD) • Lenalidomide + dexamethasone (RD) • Bortezomib + dexamethasone (VD) • Lenalidomide + bortezomib + dexamethasone (RVD) • Thalidomide + melphalan + prednisone (TMP)

  19. Q1. What is the preferred treatment regimen for Patient #1 & #2 at this point? • Thalidomide + dexamethasone (TD) • Lenalidomide + dexamethasone (RD) • Bortezomib + dexamethasone (VD) • Lenalidomide + bortezomib + dexamethasone (RVD) • Thalidomide + melphalan + prednisone (TMP) Answers 1-4 are correct, although most people would use a bortezomib-containing regimen in patients with high-risk disease. In general, answers 3 and 4 are best. Answer 5 is incorrect since treatment with melphalan will disqualify this patient as a candidate for SCT.

  20. Multiple Myeloma Treatment Linesa Maintenance Front-line treatment Relapsed Consolidation Induction Maintenance Rescue SCT Observation IMID: Thal, Len ProteasomeInh: Bor Steroids: Dex-Pred IMID:Thal-Len ProteasomeInhibitor: Bor-Car Steroids: Dex-Pred Alkylator: Cyclo-Mel Anthracycline: LipoDox-Dox IMID: Thal-Len-Pom ProteasomeInh: Bor-Car Steroids: Dex-Pred Alkylators: Mel-Cy-Benda Investigational aTransplant eligible patients. Bor = bortezomib; Dex = dexamethasone; Dox = doxorubicin; Thal = thalidomide; Len = lenalidomide; SCT = stem-cell transplant; Pred = prednisone; Lipo/Dox = liposomal doxorubicin. NCCN Clinical Practice Guidelines v2.2013.

  21. Combinations in the Upfront Treatment of MM Combination therapy incorporating novel agents results in near 100% ORRs Stewart AK et al. Blood. 2009;115:4006.

  22. Lenalidomide/Dexamethasone Efficacy CR + VGPR = 67% RajkumarSV et al. Blood. 2005;106:4050. Lacy MQ et al. Mayo Clinic Proc.2007;82:1179-1184.

  23. <?xml version="1.0"?><AllQuestions /> <?xml version="1.0"?><AllResponses /> <?xml version="1.0"?><Settings><answerBulletFormat>Numeric</answerBulletFormat><answerNowAutoInsert>No</answerNowAutoInsert><answerNowStyle>Explosion</answerNowStyle><answerNowText>Answer Now</answerNowText><chartColors>Use PowerPoint Color Scheme</chartColors><chartType>Horizontal</chartType><correctAnswerIndicator>Checkmark</correctAnswerIndicator><countdownAutoInsert>No</countdownAutoInsert><countdownSeconds>10</countdownSeconds><countdownSound>TicToc.wav</countdownSound><countdownStyle>Box</countdownStyle><gridAutoInsert>No</gridAutoInsert><gridFillStyle>Answered</gridFillStyle><gridFillColor>255,255,0</gridFillColor><gridOpacity>50%</gridOpacity><gridTextStyle>Keypad #</gridTextStyle><inputSource>Response Devices</inputSource><multipleResponseDivisor># of Responses</multipleResponseDivisor><participantsLeaderBoard>5</participantsLeaderBoard><percentageDecimalPlaces>0</percentageDecimalPlaces><responseCounterAutoInsert>No</responseCounterAutoInsert><responseCounterStyle>Oval</responseCounterStyle><responseCounterDisplayValue># of Votes Received</responseCounterDisplayValue><insertObjectUsingColor>Red</insertObjectUsingColor><showResults>Yes</showResults><teamColors>Use PowerPoint Color Scheme</teamColors><teamIdentificationType>None</teamIdentificationType><teamScoringType>Voting pads only</teamScoringType><teamScoringDecimalPlaces>1</teamScoringDecimalPlaces><teamIdentificationItem></teamIdentificationItem><teamsLeaderBoard>5</teamsLeaderBoard><teamName1></teamName1><teamName2></teamName2><teamName3></teamName3><teamName4></teamName4><teamName5></teamName5><teamName6></teamName6><teamName7></teamName7><teamName8></teamName8><teamName9></teamName9><teamName10></teamName10><showControlBar>All Slides</showControlBar><defaultCorrectPointValue>0</defaultCorrectPointValue><defaultIncorrectPointValue>0</defaultIncorrectPointValue><chartColor1>187,224,227</chartColor1><chartColor2>51,51,153</chartColor2><chartColor3>0,153,153</chartColor3><chartColor4>153,204,0</chartColor4><chartColor5>128,128,128</chartColor5><chartColor6>0,0,0</chartColor6><chartColor7>0,102,204</chartColor7><chartColor8>204,204,255</chartColor8><chartColor9>255,0,0</chartColor9><chartColor10>255,255,0</chartColor10><teamColor1>187,224,227</teamColor1><teamColor2>51,51,153</teamColor2><teamColor3>0,153,153</teamColor3><teamColor4>153,204,0</teamColor4><teamColor5>128,128,128</teamColor5><teamColor6>0,0,0</teamColor6><teamColor7>0,102,204</teamColor7><teamColor8>204,204,255</teamColor8><teamColor9>255,0,0</teamColor9><teamColor10>255,255,0</teamColor10><displayAnswerImagesDuringVote>Yes</displayAnswerImagesDuringVote><displayAnswerImagesWithResponses>Yes</displayAnswerImagesWithResponses><displayAnswerTextDuringVote>Yes</displayAnswerTextDuringVote><displayAnswerTextWithResponses>Yes</displayAnswerTextWithResponses><questionSlideID></questionSlideID><controlBarState>Expanded</controlBarState><isGridColorKnownColor>True</isGridColorKnownColor><gridColorName>Yellow</gridColorName><AutoRec></AutoRec><AutoRecTimeIntrvl></AutoRecTimeIntrvl></Settings> <?xml version="1.0"?><AllAnswers /> Lenalidomide/Bortezomib-based Rx Hematologic toxicity is more severe with addition of chemo, but not cumulative Risk of DVT does not appear to be increased over lenalidomide alone Risk of PN does not appear to be increased over bortezomib alone Generally well tolerated, although TRM with VDCR (2 patients in Evolution Study) RVD = lenalidomide/bortezomib/dexamethasone; RVDD = RVD with pegylated liposomal doxorubicin; VDCR = RVD plus cyclophosphamide; VTD = bortezomib/thalidomide/dexamethasone 1. Richardson PG et al. Blood.2010;116:679-686. 2. Jakubowiak AJ et al. Blood. 2011;118:535-543. 3. Kumar S et al. Blood. 2009:114:1729-1735.

  24. Frontline Therapy for MM with RVD Regimen • RVD is highly effective for previously untreated MM • The first regimen to result in a 100% response rate (≥PR) without ASCT • Remarkably high rates of CR/nCR and ≥VGPR • Promising outcomes data; estimated 24-month PFS of 68% and OS of 95% with RVD ± ASCT • Favorable tolerability over a lengthy treatment period • Manageable toxicities • Only 2% G3 sensory PN, 6% DVT; no treatment-related mortality • All-grade PN 80%, but mainly G1/2 and reversible • Stem cell mobilization feasible and successful in almost all patients Richardson et al.Blood. 2010;116:679-686; Anderson, et al. J ClinOncol. 2010;28:15s(suppl; abstr 8016).

  25. What Toxicities Should You Monitor in These Patients?IMID-associated Deep Venous Thrombosis • Pathophysiology unclear • MM, unlike solid tumor does not express tissue factor • Platelet activation via cathepsin G • Prevention is key • Low risk aspirin • High risk anticoagulation • High dose dex, immobility, prior DVT, comorbidity • Pearls • Continue until at least 1-2 months post completion • Do not forget to bridge for surgical procedures • Not a reason to abandon treatment Palumbo A et al. Blood Rev. 2011;25:181-191. Richardson PG et al. Leukemia. 2012;26:595-608.

  26. Other Toxicities: Peripheral Neuropathy • Peripheral neuropathy (PN) – one of the most important complications of MM treatment • PN can be caused by MM itself, and particularly by certain therapies, including bortezomib, thalidomide, vinca alkaloids, and cisplatin • Up to 20% of MM patients have PN at diagnosis, and as many as 75% may experience treatment-emergent PN during therapy • Bortezomib causes any grade PN in 31% to 47% patients • Lower-than-expected rates of severe PN with bortezomib plus lenalidomide combinations, with grade 3 PN rates of 3% and 2% with bortezomib, lenalidomide, and dexamethasone (RVD) in frontline and relapsed/refractory patients, respectively Palumbo A et al. Blood Rev. 2011;25:181-191. Richardson PG et al. Leukemia. 2012;26:595-608.

  27. Q2. What are the factors to consider when choosing supportive care for a patient treated with lenalidomide/dexamethasone alone? • You must start some form of DVT prophylaxis • You must start acyclovir • Infections are possible • High-dose dexamethasone is preferable in the younger patients • A history of DVT is an absolute contraindication • The risk of PN is minimal • Long-term complications might include diarrhea and fatigue

  28. Q2. What are the factors to consider when choosing supportive care for a patient treated with lenalidomide/dexamethasone alone? You must start some form of DVT prophylaxis You must start acyclovir Infections are possible High-dose dexamethasone is preferable in the younger patients A history of DVT is an absolute contraindication The risk of PN is minimal Long-term complications might include diarrhea and fatigue Note: According to the updated ASCO guidelines, patients receiving dexamethasone should receive VTE prophylaxis.

  29. Q3. Would you recommend autologous transplantation for Patient #1 & #2 and at what point would you recommend it? • Recommend participation in a clinical trial • Offer autologous transplantation after successful induction therapy • Allogeneic transplantation after successful induction • RVD therapy without collection of stem cells or a planned maintenance strategy

  30. Q3. Would you recommend autologous transplantation for Patient #1 & #2 and at what point would you recommend it? • Recommend participation in a clinical trial • Offer autologous transplantation after successful induction therapy • Allogeneic transplantation after successful induction • RVD therapy without collection of stem cells or a planned maintenance strategy

  31. AutologousvsAllogeneic AUTOLOGOUS • High-dose therapy with reinfusion of own cryopreserved cells • Safer, TRM <5% • Possible contamination with malignant cells • No graft-vs-malignancy effect • Higher risk of relapse ALLOGENEIC • Immunosuppressive Rx with infusion of cells from another person • Risk of rejection, GVHD • Higher risk, TRM 10%-40% • Graft-vs-malignancy occurs • Lower risk of relapse • Can perform in diseases in which blood and BM involved

  32. Autologous Transplantation vs Conventional Chemotherapy for Newly Diagnosed Myeloma Pts (n) 116 123 274 274 100 100 96 94 83 81 200 201 CR (%) – 40 – 34 5 22 – – 11 30 9 44 EFS (mos) 22 49 27 18 27 19 24 34 43 20 32 OS (mos) 48 62 46% @ 48 61% @ 48 37 52% @ 60 50 55 67 67 42 55 Barlogie et al Lenhoff et al Attal et al Fermand et al Blade et al Child et al Conventional* HDT Conventional* HDT Conventional HDT Conventional HDT Conventional HDT Conventional HDT * Historical controls Fermand J. Blood. 1998;92:3131. Blade J. Blood.2001;98:815a. Barlogie B. Blood. 1997;89:789. Lenhoff S. Blood. 2000;95:7. Attal M. N Eng J Med. 1996;335:91.

  33. Is It Time for a New Early-vs-Late SCT Study? Optimal induction regimen COLLECT HD THERAPY + SCT A A A Maintenance A A A m m HARVEST AND HOLD SCT UPON RELAPSE m Risk profile

  34. 100 100 90 90 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 BMT-CTN 0102 Trial: Survival Outcomes after the First TransplantAuto-Auto vsAuto-Allo: Intent-to-treat Analysis (n=710) Progression-free SurvivalOverall Survival Auto/Auto, 80% @ 3yr Auto/Auto, 46% @ 3yr Auto/Allo, 77% @ 3yr Probability, % Auto/Allo, 43% @ 3yr P-value = 0.67 P-value = 0.19 Months 0 6 12 18 24 30 36 42 48 Auto/Auto 436 395 348 292 242 213 178 54 42 Auto/Allo 189 165 138 117 105 89 71 23 16 0 6 12 18 24 30 36 42 48 436 424 406 395 370 348 305 107 79 189 183 167 160 156 143 124 43 27 NUMBER AT RISK: Krishnan et al. Lancet Oncol. 2011;12:1195-1203.

  35. 100 100 90 90 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 0 BMT-CTN 0102 Trial: Cumulative Incidence of Disease Progression/Relapse and Treatment-related Mortality after First Transplant Progression/Relapse Treatment-related Mortality P-value < 0.001 P-value = 0.41 Auto/Auto, 46% @ 3yr Cumulative Incidence, % Auto/Allo, 40% @ 3yr Auto/Auto, 4% @ 3yr Auto/Allo, 12% @ 3yr 0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48 Months Krishnan et al. Lancet Oncol. 2011;12:1195-1203.

  36. Lenalidomide Maintenance After Transplantation McCarthy PL.J NatlComprCancNetw. 2013;11:35-42.

  37. MPR vs MEL200 vs MPR-R vs MEL200-RResponse, PFS, and OS Palumbo. Presented at: ASCO 2013.

  38. Myeloma Tales of Two Cases CASE 1 CASE 2 55-year-old female presents with asymptomatic anemia of 10 g/dL and total serum protein 10 g/L Receives RVD x 4 followed by autologous SCT and lenalidomide maintenance Achieves a CR 1 year later has reemergence of SPEP at 0.5 mg/dL What should next step be? • 55-year-old female presents with asymptomatic anemia of 10 g/dL and total serum protein 10 g/L • Receives RVD x 4 followed by autologous SCT and lenalidomide maintenance • Achieves a CR • 3 years later has reemergence of SPEP at 0.5 mg/dL • What should next step be?

  39. Types of Relapse Treatment Administered for Relapse of Progression after Autologous PBSCT Clinical Patterns of Relapses after Autologous PBSC Transplantation Alegre A et al. Haematologica. 2002;87:609-614.

  40. New Patterns of Relapse • 64 out of 153 asymptomatic patients had routine imaging available. • Twenty-five (40%) had new bone lesions by SS (n = 12), PET/CT (n = 11), or MRI (n = 2) despite absence of any prior suspicion. Zamarin D et al. Bone Marrow Transplant. 2013;48:419-424.

  41. Case 3 • A 72-year-old male is diagnosed with MM. He started with back pain which lead to the discovery of anemia (Hgb 9.1) and 3 compression fractures • A BM showed 60% kappa plasma cells • His IgG is 4200 mg/dL, kappa FLC is 79 mg/dL, beta 2 microglobulin 8, creatinine 1.0, calcium is normal • FISH shows hyperdiploidy and no -17 or -13 • He has a complicated PMH • CAD with stent 2 years previous • Depression • Type 2 diabetes, diet controlled • HTN • Obesity • Atrial fibrillation • He is retired and recently widowed

  42. Case 3 (continued) He is started on len-dex His creatinine has worsened and is now 1.7 mg/dL The patient self-reports poor PO fluid intake Len-dex is poorly tolerated – fatigue and insomnia After only one month the patient requests treatment discontinuation or change He states he is interested only “in quality of life not quantity”

  43. Case 3: What change would you recommend for this patient? • Stop treatment • Decrease lenalidomide from 25 to 10 • Stop dexamethasone alone • Decrease dexamethasone from 40 mg weekly to 20 mg weekly • B and D • Change treatment altogether

  44. Case 3: What change would you recommend for this patient? • Stop treatment • Decrease lenalidomide from 25 to 10 • Stop dexamethasone alone • Decrease dexamethasone from 40 mg weekly to 20 mg weekly • B and D • Change treatment altogether

  45. Case 3: Second-line Treatment • The patient is treated with CyBORD with lower doses of dexamethasone (20 mg weekly) • Bortezomib is given IV weekly • He tolerates well the first cycles • By cycle 3 he reports signs of early peripheral neuropathy on his feet • He also complains “his shoes don’t fit him anymore” • He complains of mild SOB

  46. SQ Administration of Bortezomib • Randomized Phase III study • 1-3 previous lines of therapy • Up to eight 21-day cycles of bortezomib • Primary response was non-inferiority (4 cy) • 222 patients assigned to receive Rx • 145 SQ and 73 IV • ORR same (42% vs42%) • After 8 cycles 52% vs52% Moreau P et al. Lancet Oncol. 2011;12:431-440.

  47. Results SQ Bortezomib • Median FU 11.8 mos, no difference in TTP • 10.4 vs 9.4 mos • One year OS 72% vs 76% • Grade 3/4 events favored SQ (57% vs 70%) • PN less common with SQ 38% vs 53% (P=0.04) • Grade 2 or worse 24% vs 41% (P=0.012) • Grade 3 or worse 6% vs 16% (P=0.026) Moreau P et al. Lancet Oncol. 2011;12:431-440.

  48. Case 3: Second-line Treatment • Bortezomib is changed to weekly SQ • Dexamethasone is lowered to 8 mg weekly • You continue on treatment and have provided 7 cycles • The patient returns for cycle 8 and is complaining of left chest wall pain; No SOB • EKG, TnT, and CxRay are fine • A day later a vesicular rash develops • You forgot to add a medication!

  49. Case 3: Treatment-related Toxicities Which of the following is true? • Cyclophosphamide causes drug rash commonly • Dexamethasone and bortezomib can elicit Steven-Johnson like syndrome • Pemphigoid lesions are common in MM • Reactivation of herpes zoster is common with proteasome inhibitors • None of the above

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