1. Please note, these are the actual video- recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content. Select slides from the original presentation are omitted where Research To Practice was unable to obtain permission from the publication source and/or author. Links to view the actual reference materials have been provided for your use in place of any omitted slides.

2. Oncology Tumor Panel Series Multiple Myeloma Oncologist and Nurse Investigators Consult on Actual Patients from the Practices of the Invited Faculty Thursday, April 23, 2015 6:15 AM – 7:45 AM Moderator Neil Love, MD Faculty Kimberly Noonan, RN, ANP, AOCN Tiffany Richards, MS, ANP-BC, AOCNP Rafael Fonseca, MD Sagar Lonial, MD

3. Oncology Tumor Panel Series

8. Cases to be Presented A 53-Year-Old Man with Multiple Myeloma (MM) Treated with RVD Followed by ASCT (Ms Richards) A 53-Year-Old Woman with Newly Diagnosed High-Risk MM (Ms Noonan) An 80-Year-Old Woman with MM and Multiple Lytic Bone Lesions (Ms Richards) A 62-year-old Woman with Relapsed MM (Ms Noonan)

10. Theme of this series Applying evidence-based oncology to individual patients

11. RVD x 3ASCT Maintenance lenalidomide/ixazomib (on a clinical trial) Oncology Treatment Timeline Case 1: A 53-Year-Old Man with MM Receives RVD Followed by ASCT (Ms Richards) Comorbidities: None Psychosocial: Cut back on the volume of his dental practice to part-time due to fatigue, flies to and from his medical appointments 2014

12. Patient Education Plan 53-year-old man with MM Goals of treatment Antitumor effects of treatment Dose and schedule Follow-up plan, including restaging Related psychosocial issues Important potential side effects/toxicities Time point: Initiation of RVD

15. Free Kappa/Lambda Ratio

16. Key Education Points for Patients with Newly Diagnosed Multiple Myeloma Induction therapy Stem cell transplant Maintenance therapy Relapsed disease Induction therapy Maintenance therapy Relapsed disease Transplant-Eligible Transplant-Ineligible

17. Stem Cell Transplant for Multiple Myeloma Autologous stem cell transplant (ASCT): Before high-dose chemotherapy or radiation therapy, stem cells are harvested from the patient's bone marrow or blood, frozen and reinfused after the intensive treatment is complete. Allogeneic stem cell transplant: Stem cells are harvested from a matched donor.

18. Getting to Minimal Residual Disease (MRD) S.S. Patient 1×10 12 Stringent CR Molecular/Flow CR ?Cure? Disease burden Newly diagnosed 1×10 8 1×10 4 0.0 CR

19. Common Induction Regimens: Transplantation Eligible RD/Rd: Lenalidomide/dexamethasone VD: Bortezomib/dexamethasone RVD: Lenalidomide/bortezomib/dexamethasone VTD: Bortezomib/thalidomide/dexamethasone CyBorD: Cyclophosphamide/bortezomib/dexamethasone

20. Key Components of Triple Therapy Proteasome inhibitors –Bortezomib –Carfilzomib Immunomodulatory agents (IMiDs) –Lenalidomide –Pomalidomide –(Thalidomide) Corticosteroids

21. Oncology Treatment Timeline Case 1: A 53-Year-Old Man with MM Receives RVD Followed by ASCT (Ms Richards) RVD x 3ASCT Maintenance lenalidomide/ixazomib (on a clinical trial) 2014

22. Post-Transplant Maintenance Lenalidomide Study DetailsnTreatmentOutcome IFM 2005-02 1 (Median follow-up 67 mo)307 Lenalidomide Placebo PFS 46 mo 24 mo Median OS 82 mo 81 mo CALGB-100104 2 (Median follow-up 34 mo) 231 229 Lenalidomide Placebo TTP 46 mo 27 mo 3-year OS 88% 80% Palumbo et al 3 (Median follow-up 51 mo) 126 125 Lenalidomide No maintenance PFS 42 mo 22 mo 3-year OS 88% 79% 1 Attal M et al. Proc ASH 2013;Abstract 406. 2 McCarthy PL et al. N Engl J Med 2012;366:1770-81. 3 Palumbo A et al. N Engl J Med 2014;371(10):895-905.

23. Clinicaltrials.gov, April 2015 Ixazomib 3 mg po d1, 8, 15 (28-day cycle) + Lenalidomide 10 mg po qd to start (28-day cycle) May increase to 15 mg after 3 months MD Anderson Phase II Study of Maintenance Ixazomib/Lenalidomide Target accrual (n = 88) Induction therapy + ASCT with melphalan preparative regimen 60-180 days post-ASCT No more than 2 induction regimens prior to ASCT Primary Endpoint: Progression-free survival

24. Key Features of Bortezomib, Carfilzomib, Ixazomib and Oprozomib Adapted from Fostier K et al. OncoTargets and Therapy 2012;5:237-44. CompoundChemicalBindingAdmStatus BortezomibDipeptide boronateReversibleIV/SC FDA approved CarfilzomibTetrapeptide epoxyketoneIrreversibleIV FDA approved IxazomibBoronate peptideReversibleOralPhase I-III OprozomibTripeptide epoxyketoneIrreversibleOralPhase I/III

25. Ongoing Phase III Trials of Ixazomib Clinicaltrials.gov, April 2015 NDMM = newly diagnosed multiple myeloma; len = lenalidomide; dex = dexamethasone; SCT = stem cell transplant; R/R = relapsed/refractory StudyNSettingTreatment NCT01850524 (TOURMALINE-MM2) 701NDMM, transplant ineligible Ixazomib + len/dex Placebo + len/dex NCT02181413652NDMM  SCTIxazomib maintenance Placebo NCT02312258761NDMM no SCTIxazomib maintenance Placebo NCT01564537722R/R MMIxazomib + len/dex Placebo + len/dex

26. Comorbidities: None Psychosocial: Anxiety, depression 2014 CRd (carfilzomib/lenalidomide/ dexamethasone) ASCT Carfilzomib/lenalidomide maintenance (planned) Oncology Treatment Timeline Case 2: A 53-Year-Old Woman with Newly Diagnosed High-Risk MM (Ms Noonan)

28. mSMART: Mayo Stratification for Myeloma and Risk-Adapted Therapy FISH -Del 17p -t(14;16) -t(14;20) GEP -High-risk signature All others including: Hyperdiploidy t(11;14) t(6;14) FISH - t(4;14) Cytogenetic deletion 13 or hypodiploidy PCLI ≥3% High-Risk 20%Intermediate-Risk 20% Standard-Risk 60% Mikhael JR et al. Mayo Clin Proc 2013;88(4):360-76. 3 years4-5 years8-10 years

29. Patient Education Plan 53-year-old woman with high-risk MM (del17p) Goals of treatment Antitumor effects of treatment Dose and schedule Follow-up plan, including restaging Related psychosocial issues Important potential side effects/toxicities –Dyspnea/heart failure –Peripheral neuropathy –Other Time point: Initiation of CRd

30. After a median of 12 cycles: -≥PR = 98% -≥VGPR = 81% -≥nCR = 62% -sCR = 42% Grade ≥3 PN = 0% Phase I/II Study of CRd in NDMM (N = 53) CRd Cycles 9–24 CRd Induction CRd Maintenance CRd Cycles 1–4 CRd Cycles 5–8 LEN Cycles 25+ Continued lenalidomide recommended (off protocol) Transplant-eligible with ≥PR may undergo ASCT Transplant- eligible and ineligible patients Jakubowiak AJ et al. Blood 2012;120(9):1801-9.

31. Each cycle is 28 days Stem cell harvest after ≥4 cycles of CRd for patients <75 years of age Cycle 1, day 1, 2: Cfz dose is 20 mg/m 2 Cycles 1-4: Dexamethasone dose is 20 mg; cycles 5-8: Dexamethasone dose is 10 mg SD = stable disease 8 cycles CRd combination therapy Cfz 20/36 mg/m 2, 30-min infusion Day 1, 2, 8, 9, 15, 16 Lenalidomide 25 mg/day Day 1-21 Dexamethasone 20/10 mg Day 1, 2, 8, 9, 15, 16, 22, 23 SD or better? 24 cycles extended dosing Ln 10 mg/day, day 1-21 Korde N et al. Proc ASH 2013;Abstract 538. NCI Phase II Study of CRd in NDMM (N = 41)

32. ECOG-E1A11: A Phase III Study of Bortezomib or Carfilzomib with Lenalidomide and Dexamethasone for Newly Diagnosed MM Primary endpoint: Overall survival Select secondary endpoints: Progression-free survival, overall response rate, duration of response, incidence of Grade ≥2 peripheral neuropathy and cardiac toxicity R Eligibility Newly diagnosed, symptomatic standard- risk MM No prior history of Grade 2 or higher peripheral neuropathy Carfilzomib + lenalidomide + low-dose dexamethasone  limited OR finite lenalidomide maintenance Bortezomib + lenalidomide + low-dose dexamethasone  limited OR finite lenalidomide maintenance www.clinicaltrials.gov; Accessed April 2015 Protocol ID: NCT01863550 Target Accrual: 756 (open)

33. Carfilzomib Tolerability Dyspnea/cardiac effects –Role of hydration? –Use in patients with heart disease –Cardiac monitoring Use in patients with renal failure Peripheral neuropathy ?

34. Phase I Study of 30-Minute Infusion of Carfilzomib As Single Agent or in Combination with Low-Dose Dexamethasone in Relapsed and/or Refractory MM Median prior lines of therapy: 5 (range: 1-9), including: –Bortezomib: 90.9% –IMiDs: 93.9% Single-agent carfilzomib MTD: 56 mg/m 2 –ORR: 50% –Common AEs: Nausea, fatigue, pyrexia, dyspnea, thrombocytopenia Carfilzomib + low-dose dexamethasone –ORR: 55% –Safety profile similar to single-agent carfilzomib Basis for ENDEAVOR study Papadopoulos KP et al. J Clin Oncol 2015;33(7):732-9.

35. Select Ongoing Trials of Up-Front and Maintenance Therapy with Carfilzomib Clinicaltrials.gov, April 2015 Len = lenalidomide; dex = dexamethasone StudyPhaseNTreatment NCT01863550 (ECOG-E1A11) III756Carfilzomib + len + dex  len maintenance Bortezomib + len + dex  len maintenance NCT01818752 (CLARION) III882Carfilzomib + melphalan + prednisone Bortezomib + melphalan + prednisone NCT02315716II280Carfilzomib + cyclophosphamide + dex  carfilzomib maintenance NCT02203643 (FORTE) II477Carfilzomib + len + dex  len alone or with carfilzomib maintenance Carfilzomib + cyclophosphamide + dex  len alone or with carfilzomib maintenance

36. Oncology Treatment Timeline Case 3: An 80-Year-Old Woman with Standard-Risk Stage III MM (Ms Richards) Comorbidities: Hypertension Psychosocial: She is a widow with 2 supportive adult sons who accompany her to the clinic. She is an active 80-year-old patient. 2015 RVD and Zoledronic Acid

38. Patient Education Plan 80-year-old woman with MM and lytic bone lesions Goals of treatment Antitumor effects of treatment Dose and schedule Follow-up plan, including restaging Related psychosocial issues Important potential side effects/toxicities Time point: Initiation of RVD and zoledronic acid

39. Front-Line Treatment Options in the Elderly and Transplant-Ineligible Settings Rd (lenalidomide/low-dose dexamethasone) VD (bortezomib/dexamethasone) MPT (melphalan/prednisone/thalidomide) MPR (melphalan/prednisone/lenalidomide) MPV (melphalan/prednisone/bortezomib) RVD (lenalidomide/bortezomib/dexamethasone) CyBorD (cyclophosphamide/bortezomib/dexamethasone

40. Efficacy for Continuous Rd versus Rd18 versus MPT PFS: 25.5 versus 20.7 versus 21.2 months ORR: 75.1% versus 73.4% versus 62.3% Rd until progression (n = 535) Rd for 18 cycles (Rd18) (n = 541) MPT for 12 cycles (n = 547) Phase III FIRST Trial Design Facon T et al. Proc ASH 2013;Abstract 2. 1:1:1 R Eligibility (n = 1,623) Symptomatic NDMM Transplant ineligible or ≥65 years old Renal impairment allowed, but patients requiring dialysis excluded

41. Palumbo A et al. Blood 2011;118:4519-29. Preemptive Dose Reductions for Patients of Advancing Age AgentDose Level 0Dose Level -1Dose Level -2 Dexamethasone 40 mg/d d 1, 8, 15, 22 / 4 wk 20 mg/d d 1, 8, 15, 22 / 4 wk 10 mg/d d 1, 8, 15, 22 / 4 wk Melphalan 0.25 mg/kg or 9 mg/m 2 d 1-4 / 4-6 wk 0.18 mg/kg or 7.5 mg/m 2 d 1-4 / 4-6 wk 0.13 mg/kg or 5 mg/m 2 d 1-4 / 4-6 wk Thalidomide100 mg/d50 mg/d50 mg qod Lenalidomide 25 mg/d d 1-21 / 4 wk 15 mg/d d 1-21 / 4 wk 10 mg/d d 1-21 / 4 wk Bortezomib 1.3 mg/m 2 twice weekly d 1, 4, 8, 11 / 3 wk 1.3 mg/m 2 once weekly d 1, 8, 15, 22 / 5 wk Prednisone 60 mg/m 2 d 1-4 or 50 mg qod 30 mg/m 2 d 1-4 or 25 mg qod 15 mg/m 2 d 1-4 or 12.5 mg qod Cyclophosphamide 100 mg/d d1-21 / 4 wk or 300 mg/m 2 /d d 1, 8, 15 / 4 wk 50 mg/d d1-21 / 4 wk or 150 mg/m 2 /d d 1, 8, 15 / 4 wk 50 mg/d d1-21 / 4 wk or 75 mg/m 2 /d d 1, 8, 15 / 4 wk

42. Zoledronic acid (ZOL) (n = 981) R ZOL reduced skeletal-related events (SREs) vs CLO In patients with and without bone lesions at baseline ZOL reduced risk of disease progression and death vs CLO Davies FE et al. Proc ASCO 2011;Abstract 8011. Clodronate (n = 979) 1:1 MRC Myeloma IX Study Bisphosphonate continued until disease progression Eligibility (n = 1,960) Newly diagnosed Stage I-III MM

43. Kyphoplasty and Vertebroplasty in MM Used for treatment of pain related to vertebral body fractures Advantages of kyphoplasty vs vertebroplasty: Restoration of vertebral body height and a lower rate of cement extravasation Selection of patients? Santiago FR et al. World J Radiol 2014;6(6):329-43.

44. RdVD Comorbidities: None Psychosocial: She travels monthly from New York to Boston for treatment, works full-time as an administrator in a medical clinic and cares for her 93-year-old mother, while living with her husband, son, daughter-in-law and grandson. 20062008 Oncology Treatment Timeline Case 4: A 62-Year-Old Woman with Relapsed MM (Ms Noonan) Oprozomib Monitoring off treatment 2011

46. Treatment Options in the Relapsed Setting VD (bortezomib/dexamethasone) RVD (bortezomib/lenalidomide/dexamethasone) CyBorD (cyclophosphamide/bortezomib/dexamethasone) CyRD (cyclophosphamide/lenalidomide/dexamethasone) Pomalidomide (+/- dexamethasone) Carfilzomib (+/- dexamethasone) CRD (carfilzomib/lenalidomide/dexamethasone) CarPomD (carfilzomib/pomalidomide/dexamethasone)

47. Shah JJ et al. Proc ASH 2013;Abstract 690. Carfilzomib + Pomalidomide + Dexamethasone Phase I/II Dose Expansion of a Multicenter Trial of Carfilzomib and Pomalidomide with Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Target accrual (n = 82) Patients with RRMM Prior len with ≤25% response/progression during Tx or ≤60 d after completion of regimen containing len at full dose or MTD for ≥2 cycles Overall response rate: 55/79 (70%) Median PFS: 9.7 months Median OS: Not yet reached

48. Phase III ASPIRE: Carfilzomib + Lenalidomide + Dexamethasone (CRD) versus RD in Relapsed MM (N = 792) Stewart AK et al. N Engl J Med 2015;372:142-52. 26.3 mo P = 0.0001P = 0.04P < 0.001 17.6 mo 73.3% 65.0% 87.1% 66.7% ≥CR 9.3% Overall response ≥CR 31.8% CRDRD

49. ASPIRE: Adverse Events Stewart AK et al. N Engl J Med 2015;372:142-52. Discontinued treatment due to AEs –CRD: 15.3% vs RD: 17.7% Common AEs ocurring more frequently with CRD –Hypokalemia –Cough –Upper respiratory tract infection –Diarrhea No difference in incidence of peripheral neuropathy (17.1% vs 17.0%) Grade ≥3 AEs of special interest more frequent with CRD –Dyspnea –Hypertension –Cardiac failure –Pyrexia –Hypertension –Thrombocytopenia –Nasopharyngitis

50. Eligibility Relapsed/refractory MM 1-3 prior lines of therapy PR to at least 1 line of therapy Carfilzomib 30-min infusion + Low-dose dexamethasone R Bortezomib IV or SC + Low-dose dexamethasone Bortezomib IV or SC + Low-dose dexamethasone ENDEAVOR: A Phase III Study of Cd versus Vd Clinicaltrials.gov, March 2015. NCT01568866 http://www.cancernetwork.com/multiple-myeloma/endeavor-carfilzomib-doubles-pfs- relapsed-myeloma Estimated Enrollment: 898 (ongoing, not recruiting) Press Release (03/01/2015): ENDEAVOR: Median PFS 18.7 months for Cd versus 9.4 months for Vd, HR=0.53

51. Eligibility Relapsed/refractory MM 1-3 prior lines of therapy ECOG PS 0-2 Ixazomib + Lenalidomide + Dexamethasone R Placebo + Lenalidomide + Dexamethasone TOURMALINE-MM1: A Phase III Study of Ixazomib plus Len/Dex for Relapsed/Refractory MM Clinicaltrials.gov, April 2015. NCT01564537 http://www.takeda.com/news/files/20150210_02_en.pdf Estimated Enrollment: 722 (Ongoing) Press Release (2/10/2015): TOURMALINE-MM1 achieved its primary endpoint of improving PFS at the first prespecified interim analysis

52. On February 23, 2015, the FDA approved panobinostat in combination with bortezomib and dexamethasone for the treatment of patients with MM who have received at least 2 prior regimens, including bortezomib and an IMiD. Pivotal data in MM with panobinostat/bortezomib/dex versus placebo/bortezomib/dex: –Median PFS: 12.0 mos versus 8.1 mos –CR/nearCR rate: 27.6% versus 15.7% Common Grade 3/4 adverse events were diarrhea, fatigue, peripheral neuropathy and cytopenias http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm435296.htm; Richardson PG et al. Proc ASCO 2014;Abstract 8510. Panobinostat for the Treatment of MM

53. Efficacy and Safety Data of Investigational Agents in MM Phase Ib/II trial of elotuzumab in combination with lenalidomide and dexamethasone in relapsed/refractory MM (n = 73) –ORR = 84% –Median PFS = 29 months Phase I/II trial of daratumumab in combination with lenalidomide and dexamethasone in relapsed/refractory MM (n = 43) –ORR = 75% Richardson PG et al. Proc ASH 2014;Abstract 302. Plesner T et al. Proc ASH 2014;Abstract 84.