Challenging Cases in Multiple Myeloma

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. Challenging Cases in Multiple MyelomaOncologist and Nurse Investigators Consult on Actual Patients from the Practices of the Invited FacultySaturday, May 3, 20146:00 AM – 7:30 AM Faculty P Leif Bergsagel, MD Jeffrey L Wolf, MD Charise L Gleason, MSN, ANP-C, AOCNP Tiffany Richards, MS, ANP-BC, AOCNP ModeratorNeil Love, MD

3. Oncology 6-Part Case Series: Key Themes • Mechanisms of action of novel agents and tissue assays to predict response • Side effects and toxicities of novel agents; dose adjustments • Assessment and management of adherence • Specific goals of therapy and likely outcomes; sequencing of agents in advanced disease • Local and systemic complications of cancer: Fatigue, pain, CNS involvement • Care of older, frail patients and those with comorbidities

4. Oncology 6-Part Case Series: Key Themes • Clinical trials as a means to access new treatments earlier • Management of anxiety and depression • Key determinants of patient satisfaction: What do people with cancer want and need? • Quality, value and cost: Investing resources optimally • End-of-life care and planning • Impact of the cancer experience on family and loved ones, including minor children • Impact of the oncology experience on oncology health professionals

5. Agenda Two Younger Patients Who Were Candidates for ASCT • 46 yo woman who completed RVDD and has been in remission for 5 years while on maintenance lenalidomide (Ms Gleason) • 66 yo man who received RVD followed by ASCT and lenalidomide/ixazomib maintenance(Ms Richards) An Elderly Patient with Multiple Myeloma • 85 yo non-English-speaking Vietnamese man who is receiving carfilzomib/dexamethasone for relapsed disease (Ms Richards)

6. Agenda Two Patients with Relapsed Multiple Myeloma • 74 yo man with relapsed multiple myeloma and early signs of dementia (Ms Gleason) • 64 yo man with relapsed mutliple myeloma who is experiencing corticosteroid-related symptoms (Ms Richards) A Patient with Plasma Cell Leukemia and Adverse Cytogenetics • 54 yo mother of a teenage daughter who is now in complete remission (Ms Gleason)

7. Two Younger Patients Who Were Candidates for ASCT • 46 yo woman who completed RVDD and has been in remission for 5 years while on maintenance lenalidomide (Ms Gleason) • 66 yo man who received RVD followed by ASCT and lenalidomide/ixazomib maintenance (Ms Richards)

8. Case 1 (from the practice of Ms Gleason) • A 46-year-old woman was initially diagnosed with standard-risk MM in 2008, shortly after the birth of her second child • She enrolled on a clinical trial of RVDD (lenalidomide/bortezomib/dexamethasone/doxorubicin) x 8 cycles • After cycle 4, stem cells were collected for future ASCT • The patient was started on lenalidomide maintenance, which she has now received for almost 5 years • She currently lives a normal lifestyle, working out at the gym regularly and taking care of her 2 young children • She has maintained a daily journal of her experience since diagnosis

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

10. Potential curability of MM; correlation between depth of response and long-term outcome Discussion Point

11. Getting to Minimal Residual Disease (MRD) Newly diagnosed 1×1012 S.S. Patient Disease burden CR 1×108 Stringent CR 1×104 Molecular/Flow CR ?Cure? 0.0

12. Role of common genetic abnormalities in patient risk assessment and therapeutic decision-making Discussion Point

13. All others including: Hyperdiploidy t(11;14) t(6;14) mSMART: Mayo Stratification for Myeloma and Risk-Adapted Therapy • FISH • Del 17p • t(14;16) • t(14;20) • GEP • High-risk signature Standard-Risk 60% High-Risk 20% Intermediate-Risk 20% • FISH • t(4;14) • Cytogenetic deletion 13 or hypodiploidy • PCLI ≥3% 3 years 4-5 years 8-10 years Mikhael JR et al. Mayo Clin Proc 2013;88(4):360-76.

14. Rationale for the use of 3-drug combinations (versus 2) in the induction setting Discussion Point

15. Preferred Induction Regimens: Transplantation Eligible • RD/Rd: Lenalidomide/dexamethasone • VD: Bortezomib/dexamethasone • RVD: Bortezomib/lenalidomide/dexamethasone • VTD: Bortezomib/thalidomide/dexamethasone • CyBorD: Bortezomib/cyclophosphamide/dexamethasone • PAD: Bortezomib/doxorubicin/dexamethasone NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.2.2014.

16. An otherwise healthy 60-year-old patient presents with fatigue. Workup reveals Hb 9.0 g/dL, normal renal function, an M-spike with an IgG lambda component of 4.9 g/dL and bone marrow consistent with MM (ISS Stage II). Conventional cytogenetics, FISH and skeletal survey are normal. Which induction treatment would you most likely recommend for this patient? % of respondents Research To Practice Patterns of Care Study 2014 (N = 101 practicing oncologists)

17. Phase III Noninferiority Trial of Subcutaneous versus Intravenous Bortezomib SubQ Bortezomib (n = 148) N = 222 Relapsed MM 1-3 prior lines of therapy 2:1 R Intravenous Bortezomib (n = 74) Best response (up to 10 cycles): 52% vs 52% Median PFS: 9.3 vs 8.4 mo 1-yr OS: 76% vs 78% Moreau P et al. Lancet Oncol 2011;12(5):431-40. Arnulf B et al. Haematologica 2012;97(12):1925-8.

18. When administering bortezomib for the following situations, which route of administration and schedule do you generally use? INDUCTION THERAPY % of respondents Research To Practice Patterns of Care Study 2014 (N = 101 practicing oncologists)

19. SC Injection Site Rotation Within the same cycle • Injections at the same site should be avoided • Alternate between • Right and left abdomen • Upper and lower quadrantor between • Right and left thigh • Proximal and distal sites Moreau P et al. Proc ASH 2010;Abstract 312.

20. Subcutaneous (SC) Administration of Bortezomib: Local Side Effects of Injections • In a Phase III noninferiority trial of SC versus IV bortezomib: • ≥1 SC injection site reaction: 6% pts • Most common reaction: redness (57% pts) • Injection site reactions 100% resolved in median of 6 days Moreau P et al. Lancet Oncol 2011;12(5):431-40. Moreau P et al. Proc ASH 2010;Abstract 312.

21. Preventing herpes zoster reactivation in patients who are receiving bortezomib Discussion Point

22. Thromboprophylaxis in patients receiving IMiDs; other side effects; assessment of adherence to oral medications Discussion Point

23. Prophylaxis for Thromboembolism • Aspirin • None or one patient- or myeloma-related risk factor • LMWH or Full-Dose Warfarin (INR 2-3) • ≥2 patient- or myeloma-related risk factors • All patients, independent of other risk factors, receiving: • High-dose dexamethasone • Doxorubicin • Multiagent chemotherapy Palumbo A et al. Leukemia 2008;22(2):414-23.

24. Post-transplant consolidation and maintenance therapy; impact of cytogenetic profile Discussion Point

25. N Engl J Med 2012;366:1782-91. N Engl J Med 2012;366:1770-81.

26. Post-Transplant Maintenance Lenalidomide 1 Attal M et al. Proc ASH 2013;Abstract 406. 2 McCarthy PL et al. N Engl J Med 2012;366:1770-81.

27. In general, when administering lenalidomide maintenance therapy for a younger (60-year-old) otherwise healthy patient with MM who responded to induction therapy and ASCT, what is your usual preferred starting dose? % of respondents Research To Practice Patterns of Care Study 2014 (N = 101 practicing oncologists)

28. Risk of second cancers in patients receiving lenalidomide Discussion Point

29. IFM 2005-02: Second Primary Cancers (SPMs) The incidence of second primary cancers (p = 0.002): - Lenalidomide: 3.1 SPMs per 100 patient-years - Placebo: 1.2 SPMs per 100 patient-years Attal M et al. N Eng J Med 2012;366(19):1782-91.

30. CALGB-100104: Disease Progression and Second Primary Cancers At a median follow-up of 34 months, a total of 92 of the 231 patients in the lenalidomide group (40%) as compared to 133 of the 229 patients in the placebo group (58%) had progressive disease, had died or had received a diagnosis of a second primary cancer (p < 0.001). McCarthy PL et al. N Engl J Med 2012;366(19):1770-81.

31. CALGB-100104: Death At a median follow-up of 34 months, a total of 35 patients who received lenalidomide (15%) and 53 patients who received placebo (23%) had died (2-sided p = 0.03). McCarthy PL et al. N Engl J Med 2012;366(19):1770-81.

32. Case 2 (from the practice of Ms Richards) • A 66-year-old man presented with anemia and was found to have standard-risk, ISS Stage III multiple myeloma (MM) • He received lenalidomide/bortezomib/dexamethasone (RVD) x 4 cycles followed by ASCT, after which he was enrolled on a nonrandomized Phase II clinical trial of maintenance therapy with ixazomib (MLN9708) and lenalidomide • The patient is currently in complete remission and would like to travel this spring for a month-long visit to his home in Palestine

33. Patient Serum Paraprotein Levels After RVD and Transplant 2.16 Bortezomib/Lenalidomide/Dexamethasone 1.94 1.73 1.51 1.3 1.08 g/dL .86 .65 Transplant .43 .22 2/6/2014 3/9/2013 12/26/2013 3/19/2014 11/14/2013 4/20/2013 6/1/2013 7/12/2013 8/23/2013 10/4/2013 Date

34. Novel proteasome inhibitors in the management of MM Discussion Point

35. Cellular Impact of Proteasome Inhibition in Nonclinical Studies1-4 1. Proteasomes are enzyme complexes that degrade intracellular proteins in a regulated manner in all cells, both healthy and cancerous 2. Cancer cells depend upon proteins regulated by the proteasome for proliferation, metastasis and survival 3. Inhibition of the proteasome by bortezomib prevents the degradation of intracellular proteins, affecting multiple signaling cascades within cells 4. The disruption of signaling cascades in cancer cells can lead to cancer cell death and inhibit tumor growth 1 Invest New Drugs 2000;18:109-21. 2 Physiol Rev 2002;82:373-428. 3 Sci Am 2001;284:63-73. 4 Cell 1998;92:367-84.

36. Available data on carfilzomib as part of up-front induction therapy and in the relapsed setting Discussion Point

37. Phase II Study of Carfilzomib (CFZ) Monotherapy in Relapsed/Refractory MM N = 266 Relapsed/refractory MM ≥2 regimens for relapsed MM Refractory to most recent Tx including bortezomib Intravenous CFZ 20 mg/m2 twice wkly for 3 of 4 wks in cycle 1, then 27 mg/m2 for ≤12 cycles • ORR: • All patients: 23.7% • Patients with adverse cytogenetics (n = 71): 29.6% Siegel DS et al. Blood 2012;120(14):2817-25.

38. Possible Side Effects Associated with Carfilzomib • Grade ≥3 adverse events are mainly hematologic • Low rates of neutropenia • Nonhematologic adverse events include • Fatigue • Nausea • Dyspnea • Infrequent peripheral neuropathy Siegel DS et al. Blood 2012;120(14):2817-25.

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

40. Phase III ECOG-E1A11 Trial Trial Identifier: NCT01863550 Estimated enrollment: 756 (open) Carfilzomib + lenalidomide + low-dose dexamethasone  lenalidomide maintenance* R Bortezomib + lenalidomide + low-dose dexamethasone  lenalidomide maintenance* *Maintenance may be limited to 24 courses or indefinite • Primary endpoint:Overall survival for maintenance-therapy analysis • Select secondary endpoints: Progression-free survival, overall response rate, duration of response www.clinicaltrials.gov, Accessed April 2014.

41. Incidence and management of carfilzomib-associated peripheral neuropathy Discussion Point

42. Incidence and Management of CFZ-Associated Peripheral Neuropathy • CFZ is associated mostly with Grade 1/2 PN • All-grade CFZ-related PN was observed in 8.3% of patients • No Grade 4 PN observed on study • PN can be resolved with drug interruption Siegel DS et al. Blood 2012;120(14):2817-25.

43. Other rare but important toxicities with carfilzomib: pulmonary hypertension and cardiac events Discussion Point

44. Oral proteasome inhibitors in development (ixazomib, oprozomib) Discussion Point

45. Key Features of Ixazomib and Bortezomib Bortezomib Ixazomib Adapted from Fostier K et al. OncoTargets and Therapy 2012;5:237-44.

46. Phase I/II Study of Weekly Ixazomib Combined with Lenalidomide and Dexamethasone in Previously Untreated MM Maintenance Induction: up to 12 x 28-day treatment cycles 1 8 15 28 22 MLN9708 maintenance Days 1, 8, 15 28-day cycles MLN9708 MLN9708 MLN9708 Dex 40 mg Dex 40 mg Dex 40 mg Dex 40 mg Lenalidomide 25 mg, days 1–21 • ORR = 92% ≥VGPR = 55% • Grade 3 PN = 3% Kumar SK et al. Proc ASH 2012;Abstract 332.

47. Ongoing Phase I/II Trials of Oprozomib in Newly Diagnosed MM www.clinicaltrials.gov, Accessed April 2014.

48. Case 3 (from the practice of Ms Richards) • An 85-year-old Vietnamese man was diagnosed with MM in February 2013 and received melphalan/prednisone/thalidomide with the melphalan being discontinued due to episodes of neutropenia • In August 2013 he switched treatment centers and began receiving bortezomib/dexamethasone, which resulted in a response • However, therapy was stopped because of peripheral neuropathy • The patient experienced disease progression and is currently responding to carfilzomib/dexamethasone • He speaks no English and his daughter, who comes with him for clinic visits, insists on translating for him

49. Patient Serum Paraprotein Levels During Treatment Course 8.04 7.24 Bortezomib/Dexamethasone 6.43 5.63 4.82 4.02 g/dL 3.22 Carfilzomib/Dexamethasone 2.41 1.61 .8 3/5/2014 7/26/2013 2/6/2014 4/22/2014 1/9/2014 8/23/2013 9/20/2013 10/18/2013 11/14/2013 12/12/2013 Date

50. Preferred Induction Regimens: Transplantation Ineligible • Rd: Lenalidomide/low-dose dexamethasone • VD: Bortezomib/dexamethasone • MPV: Melphalan/prednisone/bortezomib • MPR: Melphalan/prednisone/lenalidomide • MPT: Melphalan/prednisone/thalidomide NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.2.2014.