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Leading the Way: Managing Multiple Myeloma for the Long -Term

Leading the Way: Managing Multiple Myeloma for the Long -Term. Accredited by Medical Education Resources Supported by The International Myeloma Foundation.

JasminFlorian
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Leading the Way: Managing Multiple Myeloma for the Long -Term

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  1. Leading the Way: Managing Multiple Myeloma for the Long -Term Accredited by Medical Education Resources Supported by The International Myeloma Foundation Grant Funding Provided by Celgene Corporation and Millennium – The Takeda Oncology Company

  2. Welcome and Introductions Beth Faiman, MSN, APRN-BC, AOCN Cleveland Clinic Taussig Cancer Institute Cleveland, OH

  3. ONS Disclaimer Meeting space has been assigned to provide a satellite symposium supported by the International Myeloma Foundation via an unrestricted educational grant during the Oncology Nursing Society’s (ONS) 34th Annual Congress, April 30 to May 3, 2009, in San Antonio, TX. The Oncology Nursing Society’s assignment of meeting space does not imply product endorsement, nor does the Oncology Nursing Society assume any responsibility for the educational content of the symposium.

  4. Symposium Accreditation • This continuing education activity provides 2.0 contact hours. • Medical Education Resources is an approved provider of continuing nursing education by the Colorado Nurses Association, an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation. • Please complete the CE Certificate Registration and Program Evaluation Form found in your guidebook and return it to the registration desk.

  5. Additional Accreditation Additional 3.8 CEU accreditation opportunity – Clinical Journal of Oncology Nursing (CJON) June 2008 supplement publication of the International Myeloma Foundation’s (IMF) Nurse Leadership Board (NLB) ‘Consensus Statements’ located at your table

  6. Chair: Beth Faiman, MSN, APRN-BC, AOCN Cleveland Clinic Taussig Cancer Institute Cleveland, OH Faculty Faculty: Joseph D. Tariman, PhC, MN, APRN-BC, OCN University of Washington Seattle, WA Sandra Rome, RN, MN, AOCN Cedars-Sinai Medical Center Los Angeles, CA Tiffany Richards, MS, ANP, AOCNP MD Anderson Cancer Center Houston, TX

  7. Agenda

  8. Learning Objectives • Describe updated data on novel agents used in the management of patients with multiple myeloma (MM) • Discuss critical issues in nursing management and medical implications of major side effect management with novel therapies in MM. • Understand the value of Survivorship Care planning, education and care. • Describe known and potential late side effects of MM and its treatment. • Identify ways to improve quality of care.

  9. Multiple Myeloma: A Current Perspective • Etiology of multiple myeloma (MM). • Epidemiology of MM. • Current and novel therapies in the management of MM.

  10. What Is Multiple Myeloma? • Cancer of plasma cells. • Healthy plasma cells produce antibodies or immunoglobulins. • Part of our humoral immunity, they are released in response to foreign body invasion. • Myeloma cells produce abnormal immunoglobulin. • Overproduce monoclonal protein or paraprotein. • Ineffective immunoglobulins. • Leads to decreased bone marrow function. • Destruction of bone tissue. San Miguel JF, et al. Pathogenesis of Multiple Myeloma: Rationale for New and Novel Therapies. Clinical Care Options:http://clinicaloptions.com/Oncology/Treatment%20Updates/Myeloma/Modules/Pathophysiology/Pages/Page%203.aspx.

  11. Myeloma Cells Are Distinguished From Normal Plasma Cells by the Presence of Large Nuclei That Are Often Eccentric Vescio R. Multiple Myeloma & Amyloidosis Program,Jonsson Comprehensive Cancer Center/Cedars–Sinai Medical Center, 2005.

  12. Multiple Myeloma: Abnormal Proliferation of Malignant Plasma Cells Kyle and Rajkumar, N Engl J Med 2004;351:1860-1873

  13. Multiple Myeloma: Epidemiology • Second most common hematological malignancy. • Incidence and rates: • 1% of all cancers • US incidence: 19,900 new cases per year • US prevalence: 100,000 patients • Deaths: estimated 10,790 per year • More than 80% of affected patients >age 60. • Affects slightly more men than women (1.6:1). Merck Manual Professional. 2005; George ED, et al. Am Fam Phys. 1999;59(7):1401-1405.

  14. Clinical Manifestations of Multiple Myeloma • Overproliferation of plasma cells can cause: • Risk of infection • Osteolytic bone lesions • Hypercalcemia • Bone marrow suppression (pancytopenia) • Renal complication risk • Production of monoclonal M proteins causes: • Decreased levels of normal immunoglobulins • Hyperviscosity http://myeloma.org/pdfs/ph07-eng_f2.pdf

  15. Major Symptoms at Diagnosis • Bone pain - 58% • Fatigue - 32% • Weight loss - 24% • Paresthesias - 5% • Asymptomatic - 11% Kyle RA. Mayo Clin Proc 2003;78:21

  16. Common Sites for Bone Involvement Skull Spine Thoracic Lumbar Vertebrae Pelvis Long bones Spinal cord – compression can occur http://www.emedicine.com/Radio/topic460.htm#section~Introduction

  17. Criteria for Diagnosis of Multiple Myeloma • Monoclonal plasma cells present in the bone marrow ≥10%, and/or presence of a documented plasmacytoma. + • Presence of M component in serum and/or urine.*+ • One or more of the following (CRAB criteria): • Calcium elevation (serum calcium >11.5 mg/dL) • Renal insufficiency (serum creatinine >2 mg/dL) • Anemia (hemoglobin <10 g/dL or 2 g/dL <normal) • Bone disease (lytic lesions or osteopenia) • *Monoclonal M spike on electrophoresis IgG >3.5 g/dL, IgA >2 g/dL, light chain >1 g/dL in 24-hour urine sample. Durie et al for the International Myeloma Working Group. Leukemia. 2006:1-7.

  18. Diagnostic Evaluation of Multiple Myeloma Alb = albumin; CBC = complete blood count; Creat = creatinine; Hgb = hemoglobin; MRI = magnetic resonance imaging; WBC = white blood cell. Abella. Oncology News International. 2007;16:27;Barlogie et al. In: Williams Hematology. 7th ed. 2006:1501; Durie et al. Hematol J. 2003;4:379; MMRF. Multiple Myeloma: Disease Overview. 2006. www.multiplemyeloma.org; Rajkumar et al. Blood. 2005;106(3):812.

  19. Durie-Salmon Staging System for Multiple Myeloma Subclassification criteria: A Normal renal function (serum creatinine level <2.0 mg/dL) B Abnormal renal function (serum creatinine level 2.0 mg/dL) Durie and Salmon, Cancer 1975;36(9):842-854

  20. International Staging System for Symptomatic Multiple Myeloma 2M=serum 2 microglobulin in mg/dL; ALB=serum albumin in g/dL Greipp PR, et al. Blood 2005; 102: 190a

  21. Challenges in MM Management • Currently incurable in most patients. • Long-term complete responses are rare. • Median survival with standard therapy is about 3 years. • Autologous stem cell transplant may prolong progression free survival, but it’s not curative. • Treatment of relapse: • No standard therapy. • Existing options inadequate. New treatment options needed. NCCN Practice Guidelines; Rajkumar et al. Mayo Clin Proc. 2002;77:813-822.

  22. MM Treatment Options • Conventional chemotherapy: • Melphalan • Doxorubicin • Cyclophosphamide • Steroid therapy: • Dexamethasone • Prednisone • Novel therapeutics: • Thalidomide • Lenalidomide • Bortezomib • Stem cell transplantation: • Autologous • Allogenic • Radiation therapy Thalomid® Prescribing Information, Revlimid® Prescribing Information; Velcade® Prescribing Information

  23. Update on Novel Therapies Joseph Tariman, PhC, MN, APRN-BC, OCNUniversity of Washington Seattle, WA

  24. NCCN Review Categories *Combinations recently reviewed by NCCN Generic Name Trade Name Bortezomib Velcade Lenalidomide Revlimid Thalidomide Thalomid NCCN Categories of Evidence and Consensus: 1 High-level evidence, uniform consensus 2A Lower-level evidence, uniform consensus 2B Lower-level evidence, non-uniform consensus NCCN Clinical Practice Guidelines in Oncology, v2 2009

  25. Recent and Ongoing Clinical Studies • Transplant-eligible patients • Bortezomib/Thalidomide/Dexamethasone (VTD) vs Thalidomide/Dexamethasone (TD) • Bortezomib/dexamethasone • Lenalidomide/low-dose Dexamethasone (Rd) • Transplant-ineligible patients • VISTA: Bortezomib/Melphalan/Prednisone (VMP) vs Melphalan/Prednisone (MP) • Lenalidomide/low-dose Dexamethasone (Rd) • New combinations and early studies • Transplant-eligible patients • Bortezomib/Lenalidomide/Dexamethasone • Bortezomib/Lenalidomide/Dexamethasone vs Bortezomib/Dexamethasone • Transplant-ineligible patients • MTP vs MPR (Phase III) • VMP vs Bortezomib/Thalidomide/Prednisone (VTP) (Phase III) • Early studies • Bortezomib/Vorinostat (Phase I)

  26. VTD vs. TD in Patients Who Are Transplant Eligible Phase III Bortezomib-Thalidomide-Dexamethasone (VTD) vs Thalidomide-Dexamethasone (TD) Prior to Stem Cell Transplantation (SCT)) • Study objective • VTD vs TD in preparation for autologous stem cell transplantation (ASCT) • Study design • Randomized trial • Three cycles of induction therapy • Methods • Pts. randomized to either VDT (n=199) or TD (n=200). • Stem cells were collected. • Consolidation therapy with same treatment to pts. • Results drawn from a final analysis of 399 patients. Cavo et al. Blood 2008 112: Abstract 158

  27. Conclusions From VTD vs. TD • Prophylaxis • Acyclovir prophylaxis against reactivation of VZV. • TEE prophylaxis with low molecular weight heparin, aspirin, or warfarin; fixed low-dose warfarin is effective. • Conclusions: • In comparison with TD, 3 21-d cycles of VTD as primary therapy significantly increased CR+nCR rates. • These response rates translated into significantly higher CR+nCR after first ASCT in the VTD arm. • Combinations of novel induction agents, such as VTD, can have a remarkable impact on both pre- and post-ASCT clinical outcome. Cavo et al. Blood 2008 112: Abstract 158

  28. Bortezomib and Dexamethasone Prior to ASCT in Transplant-Eligible Patients • Phase III, active control, multicenter, open label, randomized • Objective: compare the CR rate with vincristine/adriamycin/dexamethasone (VAD) and bortezomib/dexamethasone combinations as induction therapy. • Number of severe AE was similar between the arms: Harousseau et al, Blood 2007 110: Abstract 450.

  29. Conclusions From Bortezomib and Dexamethasone Prior to ASCT • Post-induction complete remission (CR) was increased by VD compared to VAD. • One-year PFS and OS rates were 93% and 97% with VD and 90% and 95% with VAD, respectively. Harousseau et al, Blood 2007 110: Abstract 450.

  30. VISTA Trial: VMP vs MP in Transplant-Ineligible Patients A Phase 3 Study Comparing Bortezomib/Melphalan/Prednisone (VMP) With Melphalan/Prednisone (MP) • Study objective: • Define the differences in efficacy and outcome between VMP vs MP • Study design and method: • VMP arm (IV Bortezomib in combination with oral prednisone and oral melphalan) vs MP arm (oral melphalan and prednisone) • Primary endpoint: • Time to progression (TTP) • Secondary endpoints: • Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), time to progression (TTP) and duration of response (DOR), andsafety San Miguel et al Blood 2007 110: Abstract 76; San Miguel et al Blood 2008 112: Abstract 650; Harousseau et al Blood 2008 112: Abstract 650 Mateous et al. Haematologica 2008; 93(4), 560-565

  31. VISTA Trial: VMP vs. MPMost Common Adverse Events (in ≥30% Patients) receiving VMP (n=60) Mateos, et al. Haematologica 2008; 93(4) 560-565

  32. VISTA: Updated Results OS 100 VMP 90 MP 80 70 60 Pts w/o Event (%) 50 40 Median follow-up: 25.9 mosVMP: median OS not reached (75 deaths); 3-yr OS rate: 72%MP: median OS not reached (111 deaths); 3-yr OS rate: 59% HR = 0.644; P = .0032 30 20 10 0 Months 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 • VMP associated with ~36% reduced risk of death. • 43% of pts in the MP arm who had subsequent therapy received Bortezomib upon disease progression. • Pts who received >4 cycles of Bortezomib: • 1- and 2-yr OS: 98.5% and 89%, respectively San Miguel JF, et al. Blood 2008 112: Abstract 650.

  33. VISTA Trial: VMP vs. MP These results establish VMP as another option for patients not eligible for SCT. Conclusions • Adverse events • 46% with VMP • 36% with MP • Patients remained on therapy longer with VMP: • 46 weeks with VMP • 39 weeks with MP • Patients had a longer time to next therapy. • Patients also had longer treatment-free survival. San Miguel et al Blood 2007 110: Abstract 76; San Miguel et al. Blood 2008 112: Abstract 650.

  34. Lenalidomide/Dexamethasone (RD) vs Lenalidomide/Low-Dose Dexamethasone (Rd) in Transplant-Ineligible Patients • Randomized multicenter Phase III ECOG E4A03 study • RD arm (223 patients) • Lenalidomide 25 mg (days 1-21) • Dexamethasone 40 mg (days 1-4,9-12,17-20) • Rd arm (222 patients) • Lenalidomide 25 mg (days 1-21) • Dexamethasone 40 mg (days 1,8,15,22) • Primary endpoint: response rate at 4 months Rajkumar et al, Blood 2007 110: Abstract 74

  35. Results From Lenalidomide/Dexamethasone (RD) vs Lenalidomide/Low-Dose Dexamethasone (Rd) Rajkumar et al, Blood 2007 110: Abstract 74; Jacobus et al., Blood 2008 112: Abstract 1740

  36. Results From RD vs Rd • Rd is associated with superior OS compared to RD in NDMM patients. • Increased mortality in RD arm is due to disease progression as well as increased toxicity. • Prevention of venous thrombotic events is a priority for both combinations. Rajkumar et al, Blood 2007 110: Abstract 74; Jacobus et al., Blood 2008 112: Abstract 1740

  37. Emerging New Treatments in Early Development • Single agents are limited in efficacy, likely to be used in combinations. • Bortezomib, lenalidomide, and thalidomide are being explored for combination regimens. • Combining agents directed at different targets may provide synergistic response without an increase in side effects. ASH 2008 Highlights for Physicians

  38. Bortezomib/Lenalidomide/Dexamethasone in Patients Who Are Transplant Eligible • First-line Phase I/II study assesses safety and efficacy (66 patients). • Lenalidomide 15 to 25 mg (days 1-14) • Bortezomib 1.0 to 1.3 mg/m2 (days 1, 4, 8, 11) • Dexamethasone 40/20-mg (cycles 1-4/5-8) (days 1, 2, 4, 5, 8, 9, 11, 12) • Up to 8 21-day cycles • Manageable toxicities • All G3/4 hematological (3-15%) • G3 hypophosphatemia (8%) • DVT/pulmonary embolism (5% with daily aspirin) • No treatment-related mortality • Overall response rate was 98% (at maximum planned dose – 100%) • VGPR 71% • CR/nCR 36% VRD was efficacious and well-tolerated in NDMM patients. Richardson et al, Blood 2008 112: Abstract 92

  39. Bortezomib/Lenalidomide/Dexamethasone vs Bortezomib/Dexamethasone Study in Transplant-Eligible Patients • Randomized, multicenter Phase III study ECOG E1A05 (initiated in August 2008) • Consolidation therapy for patients after dexamethasone- based induction. • VRD regimen • Bortezomib 1.3 mg/m2 (days 1, 4, 8, 11) • Lenalidomide 15 mg (days 1-14) • Dexamethasone 40 mg (days 1, 8, 15) • VD regimen • Bortezomib 1.3 mg/m2 (days 1, 4, 8, 11) • Dexamethasone 40 mg (days 1, 8, 15) • Primary endpoint: PFS • SCT is deferred until relapse • The strategy will further prolong survival. Fonseca and Rajkumar, Clin Lymphoma and Myeloma 2008 5: 315-317

  40. MPT vs MPR in Patients Who Are Transplant Ineligible • Randomized multicenter Phase III ECOG E1A06 study • MPT regimen • Melphalan (days 1-4) • Prednisone (days 1-4) • Thalidomide (days 1-28) • MPR regimen • Melphalan (days 1-4) • Prednisone (days 1-4) • Lenalidomide (days 1-21) • 28 days for up to 12 cycles • Primary objective: PFS, OS http://clinicaltrials.gov/ct2/show/NCT00602641?term=e1a06&rank=1

  41. VMP vs. VTP Exploring Alkylating (Melphalan) and Immunomodulatory (Thalidomide) Combinations With Bortezomib in Phase III Study in Elderly Transplant-Ineligible Patients • Study Design • VMP Arm (80 patients): • IV Bortezomib 2x weekly for 1 6-week cycle • IV Bortezomib 1x weekly for 5 5-week cycles + oral Melphalan/Prednisone 1xd on days 1-4 of each cycle • VTP Arm (87 patients): • IV Bortezomib 2x weekly for 1 6-week cycle • IV Bortezomib 1x weekly for 5 5-week cycles + oral Prednisone 1xd and continuous Thalidomide on days 1-4 of each cycle • Primary End Point • Overall response rate (ORR) Mateos et al. Blood 2008 112: Abstract 651

  42. Conclusions From VMP vs. VTP 6 cycles: 31 weeks of treatment) • Incidence of non-hematological AE (especially cardiac) was higher in the VTP arm, resulting in more serious AEs and treatment discontinuations • Thalidomide may not be a partner of choice for Bortezomib • - Lenalidomide should be explored Mateos et al. Blood 2008 112: Abstract 651

  43. Bortezomib and Vorinostat in Early Clinical Studies • Vorinostat (Zolinza): a synthetic inhibitor of the histone deacetylases (HDACs) • Inhibits cell cycle and survival of cancer cells • FDA-approved for some types of lymphoma • Study design: • Non-randomized, open label, parallel assignment, safety study, treatment, uncontrolled • 34 patients with relapsed/refractory MM • Objectives: • Primary: MTD • Secondary: safety and tolerability as measured by disease progression or unacceptable toxicity during each treatment cycle Weber et al, Blood 2008 112: Abstract 871

  44. Vorinostat Plus Bortezomib: Conclusions Combination of Vorinostat plus Bortezomib is active for treatment of multiple myeloma in the early study. Weber et al, Blood 2008 112: Abstract 871

  45. Future Direction of New Therapy Combinations & Protocols of Novel Therapies • New combinations of novel therapies may offer personalized targeted therapy by inhibiting specific pathways in myeloma development • Bortezomib and Thalidomide have moved from the relapsed/refractory indications to first-line therapy positions • Lenalidomide is expected to follow • The trend is to use novel drugs and established chemotherapies in combinations • MM is perceived as a chronic, long-term disease ASH 2008 Highlights for Physicians

  46. Conclusions • Novel combination therapies have great potentials in improving response rate, time to progression, progression-free survival, and overall survival outcomes. • Randomized clinical trials are needed to compare which of these novel combinations will offer patients better OS balanced with a good quality of life.

  47. Management and Treatment of Emergent Side Effects and Defining Long-Term Effects of Multiple Myeloma Beth Faiman, MSN, APRN-BC, AOCNCleveland Clinic Taussig Cancer Institute Cleveland, OH

  48. Five Major Categories of Side Effects for Novel MM Treatments • Myelosuppression • Thromboembolic events • Peripheral neuropathy • Gastrointestinal side effects • Steroid-associated side effects • Challenge for nursing management of emergent side effects: • Lack of effective practitioner-based guidelines produces a barrier to providing optimal patient care IMF-NLB ‘Consensus Statements’ CJON June 2008

  49. Myelosuppression: Definition and Symptoms • Anemia • Fatigue, malaise and SOB Red BloodCells Lymphocyte Monocyte Marrow WhiteBloodCells Eosinophil • Neutropenia • Increased risk of bacterial, fungal, and viral infections Basophil Neutrophil • Thrombocytopenia • Bruising and bleeding Platelets http://www.schneiderchildrenshospital.org/peds_html_fixed/peds/transplant/bonetran.htm; NLB Consensus Recommendations. CJON June 2008

  50. Management of Myelosuppression • General recommendations: • Monitor signs and symptoms • Monitor CBC • Educate on signs and symptoms • Myelosuppression management: • Growth factor therapy • Dose reduction as appropriate • Transfusion as indicated Adapted from NLB Consensus Recommendations. CJON June 2008 Thalomid® Prescribing Information, Revlimid® Prescribing Information, Velcade® Prescribing Information. http://ctep.cancer.gov/forms/CTCAEv3.pdf

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