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Overview of Multiple Myeloma

Overview of Multiple Myeloma. The Basics of Multiple Myeloma. This program is supported by educational grants from Celgene Corporation, Millennium: , and Onyx Pharmaceuticals. What Is Multiple Myeloma?. Cancer of the plasma cells in bone marrow Growth of myeloma cells:

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Overview of Multiple Myeloma

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  1. Overview of Multiple Myeloma

  2. The Basics of Multiple Myeloma This program is supported by educational grants from Celgene Corporation, Millennium: , and Onyx Pharmaceuticals.

  3. What Is Multiple Myeloma? • Cancer of the plasma cells in bone marrow • Growth of myeloma cells: • Disrupts normal bone marrow function • Reduces normal immune function • Results in abnormal production and release of monoclonal protein into blood and/or urine • Destroys and invades surrounding bone Barlogie B, et al. In: Williams Hematology; 2006. Durie BG. IMF 2007.

  4. Multiple Myeloma Epidemiology • Death rates • Decreased during 1991-2005 • 11.3% decrease for women, 7.25% decrease for men • Risk factors • Unknown in the majority of cases • Increased with age, male sex, obesity, and black race • Variable response to treatment and variation in survival • From a few mos to > 10 yrs • High-risk attributes are thought to play a primary role • 20% of patients survive > 10 yrs, regardless of therapy • Novel agents may neutralize the effects of some high-risk features Badros AZ. J Natl Compr Canc Netw. 2010;8:S28-S34. Kurtin S. Oncology Nurse Ed. 2011;25. Siegel R, et al. CA Cancer J Clin. 2014;64:9-29. SEER Stat Fact Sheets: Myeloma.

  5. M-protein Marrow infiltration Myeloma Can Result in a Broad Spectrum of Clinical Manifestations Renal compromise (30%) Neuropathy (33%) Hyperviscosity Amyloidosis Immune deficiency Infection (15%) Multiple myeloma cells Hypercalcemia (15% to 20%) Destruction of bone Bone pain Lytic lesions (70%) Hoffman R. Hematology: basic principles and practice, 5th edition; 2008. Ropper AH, et al. N Engl J Med. 1998;338:1601-1607. Anemia (10% to 35%)

  6. Classification of Myeloma Heavy chain: • IgG, IgA, IgD, IgM, IgE • 77% of myeloma cases • IgG and IgA most common Nonsecretory: • No detectable immunoglobulin • 1% to 2% of myeloma cases Light chain (Bence-Jones protein): • Kappa (κ) or lambda (λ) • 20% of myeloma cases Variable region Light chain Heavy chain Constant region Kumar SK, et al. Mayo Clinic Proc. 2009;84:1095-1110. Schmidt-Hieber M, et al. Haematologica. 2013;98:279-287. Serum free light chain

  7. Disease Trajectory Aggressive and Stromal Independent Nonmalignant Accumulation Malignant Transformation Plasma cell leukemia Stromaangiogenesis and IL-6dependent MGUS Smoldering Myeloma Multiple Myeloma • < 3 g M-protein • < 10% clonal BMPC • No MM-related end-organ damage • 1%/yr risk of progression to MM • ≥ 30 g/L M-protein • ≥ 10% clonal BMPC • No MM-related end-organ damage • 10%/yr risk of progression to MM in the first 5 yrs • ≥ 10% clonal BMPC • M-protein in serum and/or urine • ≥ 1 CRAB features of disease related to organ damage C: Calcium elevation > 11.5 mg/L or ULN R: Renal dysfunction (serum creatinine > 2 mg/dL) A: Anemia (Hb < 10 g/dL or 2 g < normal) B: Bone disease (lytic lesions or osteoporosis) Kuehl WM, et al. Nat Rev Cancer. 2002;2:175-187. Vacca A, et al. Leukemia. 2006;20:193-199. Agarwal A, et al. Clin Cancer Res. 2013;19:985-994. Durie BG, et al. Hematol J. 2003;4:379-398. Kurtin SE. JAdPrO, 2010;1:19-29.

  8. Role of Bone Marrow Microenvironment in Myeloma Myeloma cells IL-6TNFIL-1 Bone marrow stromal cells ICAM-1 Bone marrow vessels VEGF bFGF IL-2IFN  PBMC CD8+ T cellsNK cells Hideshima T, et al. Blood. 2000;96:2943-2950. Davies FE, et al. Blood. 2001;98:210-216. Gupta D, et al. Leukemia. 2001;15:1950-1961. Mitsiades N, et al. Blood. 2002;99:4525-4530.Lentzsch S, et al. Cancer Res. 2002;62:2300-2305.

  9. Diagnostic Evaluation Establish diagnosis of MM MGUS Smoldering Active Determine subtype Heavy chain/light chain Nonsecretory Solitary plasmacytoma Determine stage International Staging System Durie-Salmon staging system Estimate prognosis Cytogenetics Albumin β2-microglobulin Ploidy Identify need for immediate intervention Severe hypercalcemia Acute renal failure Cord compression Severe pain or impending fracture NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.2.2014. Kurtin S. JAdPrO. 2010;1:19-29.

  10. Monoclonal Protein—M Spike Normal SPEP Abnormal SPEP • Amount/type of M-protein varies among patients (IgG, IgA 80% of cases) • Abnormal M-protein (immunoglobulin) loses immune function and adheres and binds to tissues Barlogie B, et al. In: Williams Hematology; 2006. p. 1501. Durie. IMF 2007. MMRF. Intro to Myeloma. 2005.

  11. International Staging System • Serum β2m reflects tumor load and is elevated in renal failure Greipp PR, et al. J Clin Oncol. 2005;23:3412-3420.Dimopoulos M, et al. Leukemia. 2009;23:1545-1556.

  12. Cytogenetic Testing Methodologies

  13. Cytogenetic Classification • mSMART 2.0: classification of active myeloma High Risk 20% Intermediate Risk 20% Standard Risk 60% • FISH • Del(17p) • t(14;16) • t(14;20) • GEP • High-risk signature • FISH • t(4;14) • 1q gain • Complex karyotype • Metaphase deletion 13 or hypodiploidy • High PCLI All others including: • Trisomies • t(11;14) • t(6;14) OS 3 Yrs OS 4-5 Yrs OS 8-10 Yrs Dispenzieri A, et al. Mayo Clin Proc. 2007;82:323-341. Kumar SK, et al. Mayo Clin Proc. 2009;84:1095-1110. Mikhael JR, et al. Mayo Clin Proc. 2013;88:360-376.

  14. Normal Karyotypes Female Male Strupp C, et al. Leukemia. 2003;17:1200-1202.

  15. Hyperdiploidy Belurkar S, et al. Ind J Med Sci. 2013;67:188-192.

  16. Fluorescence in Situ Hybridization Analysis • t(14;20) • Chromosome 14 stained green • Chromosome 20 stained red Stralen E, et al. Leukemia. 2009;23:801-803.

  17. Gene Expression Profiling in Myeloma Decaux O, et al. J Clin Oncol. 2008;26:4798-4805.

  18. Natural History of Myeloma Asymptomatic Symptomatic 100 2. RELAPSE ACTIVE MYELOMA REFRACTORY RELAPSE M-Protein (g/L) 1. RELAPSE 50 MGUS or smoldering myeloma Plateau remission 20 First-line therapy Second-line therapy Third-line therapy Kuehl WM, et al. Nat Rev Cancer. 2002;2:175-187. Vacca A, et al. Leukemia. 2006;20:193-199. Siegel DS, et al. Community Oncol. 2009;6:12:22-29. Durie BG, et al. Hematol J. 2003;4:379-398; adapted with permission from Durie B.

  19. Survival in Myeloma Is Improving With Novel Agents 5-Yr Survival by Age 1.0 Median 7.3 yrs 0.9 0.8 0.7 2006-2010 0.6 0.5 Proportion Surviving The use of novel agent inductions with melphalan and ASCT have doubled median survival for nearly all patients 0.4 0.3 0.2 2001-2005 0.1 0 0 1 2 3 4 5 6 7 8 9 10 Follow-up From Diagnosis (Yrs) Kumar SK, et al. ASH 2012. Abstract 3972.

  20. Treatment of Multiple Myeloma Confirmed Diagnosis of Multiple Myeloma: CRAB Criteria Determination of transplant eligibility Immediate interventions for serious adverse events Individualized Treatment Selection for Induction Therapy Transplant Eligible Works rapidly (CR, nCR, VGPR) Well tolerated Spares stem cells Level of evidence: 1 or 2A Transplant Ineligible Achieving a CR or nCR Level of evidence: 1 or 2A Tolerability and QoL PS and comorbidities Continued Treatment Salvage therapy Maintenance therapy NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.2.2014.

  21. Clinical Considerations in Deciding Induction Therapy • High tumor burden • Pulse dexamethasone • Combination therapies with alkylators and IMiDS and bortezomib • Renal failure • Pulse dexamethasone • Combination therapies with alkylators and thalidomide and bortezomib (role of lenalidomide uncertain) • Hypercalcemia • Pulse dexamethasone • Bisphosphonates • Frail • Avoid high-dose dexamethasone • Clotting or bleeding history • Assess risk of use of lenalidomide/ thalidomide and anticoagulation • Preexisting neuropathy • Assess use of bortezomib/ thalidomide • Cytogenetic abnormalities • Indication for bortezomib/ lenalidomide Niesvizky R, et al. Oncology (Williston Park). 2010;24:14-21. NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.2.2014. Stadtmauer EA. Oncology (Williston Park). 2010;24:7-13.

  22. NCCN Recommendations for Adjunctive Treatment • Bone disease • Bisphosphonates (category 1) • Radiation therapy • Orthopedic consultation • Vertebroplasty or kyphoplasty • Hypercalcemia • Hydration, steroids, furosemide • Zoledronic acid preferred • Hyperviscosity • Plasmapheresis • Anemia • Consider erythropoietin • Infection • IVIG for recurrent infections • Pneumovax and influenza vaccine • PCP, herpes and antifungal prophylaxis for high-dose orlong-term steroids • Herpes zoster prophylaxis with bortezomib • Renal dysfunction • Avoid aggravating factors: contrast, NSAIDs, dehydration • Not a contraindication to HCT • Monitor bisphosphonates closely • Coagulation/thrombosis • Prophylactic anticoagulation with IMiDs NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.2.2014. Miceli T, et al. Clin J Oncol Nurs. 2011;15(suppl):9-23. Faiman B, et al. Clin J Oncol Nurs. 2011;15(suppl):66-76.

  23. Epidemiology of Multiple Myeloma • 23,500 new cases and 10,710 deaths from myeloma were expected in the United States in 2012 • More common in men than in women • Higher incidence in blacks vs whites (2:1) • Median age at diagnosis: 70 yrs Cancer facts and figures 2012. American Cancer Society; 2012. Altekruse SF, et al, eds. SEER cancer statistics review, 1975-2007. National Cancer Institute. NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.1.2013.

  24. Multistep Pathogenesis of Multiple Myeloma

  25. Natural History of Noncurable Malignancies Symptomatic Asymptomatic 100 2. RELAPSE ACTIVE MYELOMA REFRACTORY RELAPSE M-Protein (g/L) 1. RELAPSE 50 MGUS or smoldering myeloma Plateau remission 20 First-line therapy Second-line therapy Third-line therapy

  26. Clinical Manifestations of Symptomatic Multiple Myeloma Renal compromise (30%) M-protein Neuropathy (33%) Immunedeficiency Infection (15%) Hypercalcemia (15% to 20%) Destruction of bone Bone pain (75% to 80%) Marrow infiltration Lytic lesions (70%) Adapted from: Hoffman R. Hematology: Basic Principles and Practice, 5th edition; 2008. Ropper AH. N Engl J Med. 1998;338:1601-1607. Rajkumar SV. Curr Probl Cancer. 2009;33:7-64. IMF update 2003 (http://myeloma.org/ArticlePage.action?articleId=1044). Anemia (70%)

  27. Challenges in Treatment • “High-risk” disease, expected OS: 2-3 yrs • t(4;14), t(14;16), del(17p), 1q21 amplification by FISH • del(13q) by cytogenetics, hypodiploid cytogenetics • High β2-M (≥ 5.5 mg/L) • IgA, high plasma cell labeling index • Clinical treatment challenges • Renal failure • Older population, median age at diagnosis: 70 yrs • Significant comorbidities: heart, lung disease • Extramedullary disease • Managing light-chain disease

  28. Patient Assessment

  29. Diagnostic Criteria for Myeloma *C: Calcium elevation (> 10.5 mg/L or ULN)R: Renal dysfunction (serum creatinine > 2 mg/dL)A: Anemia (Hb < 10 g/dL or 2 g < normal)B: Bone disease (lytic lesions or osteoporosis) 1. IMWG. Br J Haematol. 2003;121:749-757. 2. Kyle RA, et al. N Engl J Med. 2002;346:564-569.3. Durie BG, et al. Hematol J. 2003;4:379-398.

  30. Progression to Symptomatic Myeloma • MGUS: up to 3% of persons 50 yrs of age or older and ~ 6% of those older than 70 yrs • For asymptomatic myeloma, maximum risk in the first 5 yrs 100 Smoldering Multiple Myeloma 80 78 73 66 60 Probability of Progression (%) 51 40 MGUS 20 21 4 16 10 0 0 20 15 5 25 10 Yrs Since Diagnosis Kyle RA, et al. N Engl J Med. 2007;356:2582-2590. Greipp PR, et al. J Clin Oncol. 2005;23:3412-3420.

  31. Initial Diagnostic Evaluation NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.1.2013.

  32. Symptomatic Myeloma Staging Risk factors: higher M spike, higher plasma cell burden, type of M-protein, abnormal free light-chain ratio, circulating plasma cells Kyle RA, et al. N Engl J Med. 2007;356:2582-2590. Greipp PR, et al. J Clin Oncol. 2005;23:3412-3420.

  33. Multiple Myeloma: Risk Categories *Patients with t(4;14), β2-microglobulin < 4 mg/L, and Hb ≥ 10 g/dL may have intermediate-risk disease. Kumar SK, et al.Mayo Clin Proc. 2009;84:1095-1110. Fonseca R, et al. Leukemia. 2009;23:2210-21. Kyle RA, et al. Clin Lymphoma Myeloma. 2009;9:278-288. Munshi N, et al. Blood. 2011;117:4696-4700.

  34. Effect of t(4;14), FISH Status, ISS Staging and Age on OS in Multiple Myeloma 100 80 Patients remaining alive, % 60 Patients Remaining Alive (%) A vs B: P < .0001C vs D: P < .03E vs F: P < .05 A vs B: P < .0001C vs D: P < .03E vs F: P < .05 40 20 0 0 10 5 15 Yrs From Start of Treatment Avet-Loiseau H, et al. Leukemia. 2013;27:711-717.

  35. Initial Approach to Treatment of Myeloma Transplantation candidate Nontransplantation candidate (based on age, performance score, and comorbidities) Induction treatment (nonalkylator-based induction x 4-6 cycles) Induction treatment Maintenance Stem cell harvest Stem cell transplantation Consolidation therapy ? Maintenance

  36. Case: 43-Yr-Old Male Presents With Acute Severe Lower Back Pain From Lifting Groceries Patient assessment: • X-ray of lumbar spine: L4 compression fracture, lytic disease in L2 and L5 • Blood work: Hb 9.5 mg/L, plt 178/mm3, creatinine 1.5 mg/dL, albumin 3.5 mg/dL, β2-M 3.1 mg/L, Ca 9.8 mg/dL, LDH 190 U/L • SPEP M-protein 4.5 g/dL, IgG lambda, IgG 5200 mg/dL, IgA 35 g/L, IgM 25 g/L, UPEP + lambda light chains • Bone marrow: 40% plasma cells, cytogenetics normal; FISH: no t(4;14), t(14;16), or del(17p) • Skeletal survey: multiple lytic lesions

  37. Overview of Induction Regimens

  38. Induction Therapies: Transplantation Eligible • NCCN Category 1 • Bortezomib/dexamethasone (VD) • Bortezomib/thalidomide/dexamethasone (VTD) • Bortezomib/doxorubicin/dexamethasone (PAD) • Lenalidomide/dexamethasone (RD) • NCCN Category 2A • Bortezomib/cyclophosphamide/dex (CyBorD) • Bortezomib/lenalidomide/dexamethasone (VRD) • NCCN Category 2B • Thalidomide/dexamethasone (TD) • Dexamethasone • Liposomal doxorubicin/vincristine/dexamethasone (DVD) New (3/8/2013): Carfilzomib in combination with lenalidomide and dexamethasone NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.1.2013.

  39. Phase III Trials: Novel Agent Induction for Transplantation-Eligible Patients 1. Cavo M, et al. Lancet. 2011;376:2075-2085. 2. Harousseau JL, et al. J Clin Oncol. 2010;28:4621-4629. 3. Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955. 4. Rosiñol L, et al. ASH 2011. Abstract 3962. 5. Rosiñol L, et al. Blood. 2012;120:1589-1596. 6. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.

  40. Lenalidomide/Dexamethasone Induction Followed by SCT: OS • E4A03 trial RD vs Rd • Landmark analysis: 4 mos • Early SCT after 4 cycles vs continued therapy with lenalidomide • 94% OS at 3 yrs for those undergoing SCT vs 78% for those continuing protocol therapy 94% 78% 1.0 0.9 0.8 0.7 0.6 0.5 Probability Log-rank test: Chi sq = 6.971 (P = .008) 0.4 0.3 0.2 Early SCT: no (n = 141)Early SCT: yes (n = 68) 0.1 0 0 12 24 36 48 Early SCT: no 141Early SCT: yes 68 13268 12264 5334 00 Mo Siegel D, et al. ASH 2010. Abstract 38. Reprinted with permission.

  41. VTD vs TD for SCT Induction in Newly Diagnosed Myeloma • Median follow-up: 36 mos • Estimated 3-yr OS: 86% for VTD vs 84% for TD (P = .30)[2] Progression-free survival[1] PFS[1] 100 VTD 75 TD 60% 48% 50 PFS (%) %4432 N7151 EventsTDVTD P = .042 25 HR: 0.69 (95% CI: 0.48-0.99; P = .043) 0 0 6 12 18 24 30 35 Mos From Start of Consolidation Therapy Patients at Risk, nTDVTD 161160 153154 136142 114125 8486 4353 2126 1. Cavo M, et al. Blood. 2012;120:9-19. 2. Cavo M, et al. Lancet. 2010;376:2075-2085.

  42. Case • Your 43-yr-old patient receives bortezomib/lenalidomide/ dexamethasone (VRD) for 3 cycles • Re-evaluation • M-protein not detectable in blood or urine, IFE positive • Serum free light chain: kappa 0.8 mg/dL, lambda 4.3 mg/dL • Bone marrow: 2% PC, 0.8% clonal PC by flow cytometry • Skeletal survey unchanged • CBC, creatinine, calcium within normal limits How would you treat this patient now?

  43. CR to Novel Agents Correlates With Long-term PFS and OS in Elderly Patients • Retrospective analysis of frontline treatment in 3 randomized European trials (GISMM-2001, GIMEMA MM0305, and HOVON groups; N = 1175) • Regimens: MP (n = 332), MPT (n = 332), VMP (n = 257), VMPT-VT (n = 254) PFS OS CR VGPR PR 1.0 1.0 0.8 0.8 0.6 0.6 Probability of OS Probability of PFS 0.4 0.4 0.2 0.2 P < .001 P < .001 0 0 0 24 48 72 0 24 48 72 Mos Mos Gay F, et al. Blood. 2011;117:3025-3031.

  44. Phase III Trials: Novel Agent Induction for Transplantation-Ineligible Patients *Median OS not yet reached; % alive at time of follow-up is reported. 1. Facon T, et al. Lancet. 2007;370:1209-1218. 2. Hulin C, et al. J Clin Oncol. 2009;27:3664-3670. 3. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. 4. Palumbo A, et al. N Engl J Med. 2012;366:1759-1769. 5. San Miguel JF, et al. J Clin Oncol. 2013;31:448-455.

  45. MM-015: MPR Induction Plus Lenalidomide in Newly Diagnosed Elderly MM Patients • Updated analysis of randomized, multicenter, placebo-controlled phase III trial Cycles 1-9 (28-day cycles) Stratified by age and disease stage Cycles 10+ MPR-R Melphalan 0.18 mg/kg on Days 1-4 +Prednisone 2 mg/kg on Days 1-4 + Lenalidomide 10 mg/day on Days 1-21 Continued lenalidomide Newlydiagnosedtransplantation-ineligibleMM patients65 yrsof age or older(N = 459) MPR Melphalan 0.18 mg/kg on Days 1-4 +Prednisone 2 mg/kg on Days 1-4 + Lenalidomide 10 mg/day on Days 1-21 Discontinued lenalidomide, placebo added Lenalidomide 25 mg/day ± Dexamethasone Disease progression MP Melphalan 0.18 mg/kg on Days 1-4 + Prednisone 2 mg/kg on Days 1-4 + Placebo on Days 1-21 Continued placebo Primary endpoint: PFS Open-label extension/ follow-up phase Double-blind treatment phase Palumbo A, et al. N Engl J Med. 2012;366:1759-1769.

  46. MM-015: Progression-Free Survival 65-75 Yrs of Age70% Reduced Risk of Progression All Patients 66% Reduced Risk of Progression 100 100 75 75 HR: 0.301(P < .001) MPR-R vs MPR: HR: 0.49 (P < .001) HR: 0.618(P = .006) 50 50 Patients (%) Patients (%) MPR-R vs MP: HR: 0.40 (P < .001) 25 25 0 0 0 10 20 30 40 0 5 10 15 20 25 30 35 40 Mos Mos Palumbo A, et al. ASH 2011. Abstract 475. Reprinted with permission. Data cutoff : May 11, 2010 Palumbo A, et al. N Engl J Med. 2012;366:1759-1769.

  47. MM-015: Overall Survival All Patients 65-75 Yrs of Age MPR-R MPR-R 100 100 MPR MPR MP MP 75 75 50 Patients (%) Patients (%) 50 25 25 0 0 0 0 10 20 30 40 50 0 10 20 30 40 50 Mos Mos Palumbo A, et al. ASH 2011. Abstract 475. Reprinted with permission. Data cutoff : February 28, 2011 Palumbo A, et al. N Engl J Med. 2012;366:1759-1769.

  48. VISTA: VMP vs MP in Patients With Multiple Myeloma > 65 Yrs of Age Median OS benefit: 13.3 mos 5-yr OS rates: 46.0% vs 34.4% 100 90 80 70 60 50 40 30 20 10 0 Patients Alive (%) Group n Events Median HR (95% CI) P Value MP 338 21143.1 VMP 344 17656.40.695 (0.567-0.852) .0004 0 6 12 18 24 30 36 42 48 54 60 66 72 78 Mos Pts at Risk, n 338 301 262 240 216 196 168 153 133 112 61 24 3 344 300 288 270 246 232 216 199 176 158 78 34 1 Delforge M, et al. Eur J Haematol. 2012;89:16-27.

  49. VMPT + VT Maintenance vs VMP as Frontline Therapy PFS 1.00 VMPT VMP P 5 yr PFS 29% 13% <.00015 yr TTNT 41% 19% <.00015 yr OS 61% 51% .01 0.75 Median 35.3 months Patients (%) 0.50 0.25 Median 24.8 months HR 0.58 (95% CI, 0.47-0.71, P < 0.0001) 0.00 0 10 20 30 40 50 60 70 Palumbo A, et al. ASH 2012. Abstract 200. Reprinted with permission.

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