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Treatment of Transplant Ineligible/Elderly MM Patients

Treatment of Transplant Ineligible/Elderly MM Patients. Ruben Niesvizky Department of Medicine, Division of Hematology/Oncology, Weill-Cornell Medical College / New York Presbyterian Hospital, New York, NY, USA. Myelomacenter.org run9001@med.cornell.edu. Disclosures.

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Treatment of Transplant Ineligible/Elderly MM Patients

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  1. Treatment of Transplant Ineligible/Elderly MM Patients Ruben Niesvizky Department of Medicine, Division of Hematology/Oncology, Weill-Cornell Medical College / New York Presbyterian Hospital, New York, NY, USA Myelomacenter.org run9001@med.cornell.edu

  2. Disclosures Speaker’s bureau: Celgene, Millennium, Onyx

  3. 65 year-old Hispanic male Presents to emergency room with chest pain, fatigue; found with: Creatinine: 5.0 Hemoglobin: 8.9 Multiple lytic lesions Total urine protein: 20 gm/24 hr UPEP: 19.4 gms kappa light chain SPEP: 0.1 monoclonal peak β2M: 15.0 BM: 50% plasma cells Case

  4. As you discuss with him his disease and his prognosis, he is concerned that his age precludes him from aggressive therapy. You advise him: He is a “young person with lots of experience,” and his age should not preclude him from receiving aggressive therapy with the intent of changing the natural history of his disease Patients over the age of 65 should not be considered for aggressive therapies Case Discussion

  5. Nearly half of multiple myeloma patients are considered elderly Current distinction of elderly based on transplant eligibility (European and North American trials) Patients under 65 years of age, 35% Older patients from 65 to 75 years of age, 28% Elderly patients over 75, 37% 37% 28% Elderly Older 35% The Elderly Patient The median age at diagnosis is 70 years . Palumbo A, et al. Hematology Am Soc Hematol Educ Program. 2009:566-577.; Ferlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase No. 5 Version 2.0. Lyon: IARC Press; 2004.; Ries LAG, et al. National Cancer Institute. SEER Cancer Statistics Review. Source: SEER 13. Accessed August 24, 2010 at: http://seer.cancer.gov/faststats

  6. Myeloma: 5-year Relative Survival Rates 25.2 % 42.9% < 65 years >65 years SEER 1995-2001

  7. Novel Agent Limitations in the Aging Population Median OS<65 60 m Median OS>65 32 m Kumar et al. Blood 2007

  8. Treatment of Elderly MM Patients Leading Questions • What is the goal of treatment (does CR matter)? • What is the best induction treatment? • Is it possible to individualize the treatment? • Can novel drugs improve outcome

  9. Treatment of Elderly MM Patients Leading Questions • What is the goal of treatment (does CR matter)? • What is the best induction treatment? • Is it possible to individualize the treatment? • Can novel drugs improve outcome

  10. Medline/OVID search from 1980 – Mar 2008 13 studies (4396 patients) meeting the criteria: randomized comparative trials in newly diagnoses MM reporting CR or CR/nCR and survival (either median survival or survival rate) Percent improvement in survival for each percent increase in the CR/nCR rate was calculated for each study Median not available, OS calculated from 2yr (San Miguel), 3yr (Palumbo) and 5yr (Zervas) estimates CR in Non-Transplant Setting van de Velde et al. Haematologica 2007 • 5 of 13 studies failed to show association: primarily due to the confounding effect of a therapy that generates high CR and is simultaneously too toxic • Two polarizing impact of a therapy on survival (higher CR leading to longer survival vs higher toxicity leading to shorter survival) confounds analysis

  11. Hematologic CR Correlates with Long-term PFS and OS in Elderly Patients Treated with Novel Agents • Retrospective analysis: 3 randomized European trials of GIMEMA and HOVON groups (N=1175) • First-line treatment • MP (n=332), MPT (n=332), VMP (n=257), VMPT-VT (n=254) • Significant benefit also seen when analysis is restricted to patients >75 years old OS PFS CR CR VGPR Probability Probability VGPR PR PR P<0.001 P<0.001 Gay et al. Blood 2011; 117(11):3025-31

  12. The Better the Quality of the Response the Longer the Survival (Immunophenotypic CR): GEM2005>65y PFS Immunophenotypic CR 90% at 3y “Stringent CR”38% at 3y Conventional CR57% at 3y PR (≥70% reduction)28% at 3y 100 80 60 40 20 P =0.001 0 0 10 20 30 40 50 60 Paiva et al; J Clin Oncol. 2011;29(12):1627-33. Months

  13. CR 1.00 1.00 VGPR 0.75 0.75 PR 0.50 1.00 0.50 Median 47 mo CR 0.25 0.25 0.75 0.00 0.00 0.50 0 10 20 30 40 50 60 70 80 20 40 60 80 100 12 PR 0.25 P<0.001 0.00 10 20 30 40 50 60 Sequential Approach NDMM Patients Induction PAD four 21-day courses Transplant MEL100 two courses Consolidation Len-Pdn four 28-day courses Maintenance Len until progression Median follow-up 66 months Median age 70 years PFS OS according response PFS according response VGPR months months months Gay F, et al. Gr. Emat. Milan 19 November 2012 PAD, bortezomib-pegylated doxorubicin-dexamethasone; MEL100, Melphalan100 mg/m2; Len-Pdn, lenalidomide-prednisone; Len, lenalidomide; PFS, progression-free survival; OS, overall survival; CR, complete response; VGPR, very good partial response; PR, partial response; NDMM, newly diagnosed multiple myeloma

  14. Important Aim of Treatment: Achievement of high-quality, sustained CR balanced with acceptable toxicity CR Should Be an Important Objective in Elderly MM Patients

  15. Treatment of Elderly MM Patients Leading Questions • What is the goal of treatment (does CR matter)? • What is the best induction treatment? • Is it possible to individualize the treatment? • Can novel drugs improve outcome

  16. THALIDOMIDE

  17. MPT vs. MP : Efficacy in Newly Diagnosed Elderly Myeloma Patients • 3 trials (IFM991, IFM012, HOVON3)………. > RR, PFS & OS • 2 trial (GIMEMA4, TURKISH5)………………. > RR, PFS • 1 trial (Nordic6 )…………………………….. > RR RR : 59% vs. 37 % (>22%) CR : 10% vs. 2,5% (>8 %) PFS : 20,4 vs. 15 m ( 6 m)………… HR 0,67 OS : 39,3 vs. 32,7 m (>6 m)…………HR 0,83 • Thal maintenance in Italian, Nordic, Hovon • Facon et al. Lancet 2007;370:1209–1218; 2. Hulin et al. JCO 2009; 27(22):3664-70; 3. Wijermans JCO 2010; 28: 3160-6; 4. Palumbo et al. Blood 2008; 112: 3107–3114;5. Beksac M et al. Eur J Haematol 2010; 86:16-22; 6. Waage et al Blood 2010;116(9):1405-12; Fayers PM et al. Blood 2011; 118(5): 1239-47

  18. MPT vs. MP : Toxicity *Appropriate thromboprophylaxis is required ** p of significant value Palumbo A. Haematologica 2012; Epub ahead on August 8

  19. Other Thalidomide-based Combinations in Front-line Study Results Reference Morgan et al. Blood 2011; 118(5): 1231-8 Phase 3 CTDa vs MP Phase 3 Thal/dex vs MP Ludwig et al. Blood,2009 ;113:3435-43 • In patients > 75 years, OS longer with MP (41 vs 20m) • In patients <75 years, similar OS • Higher mortality during 1st y with thal/dex vs MP (28 vs 16, p=0.02) Thal: 200 mg daily; Dex: 40 mg days 1-4; 9-12

  20. LENALIDOMIDE

  21. Phase III Study Scheme N=459 patients > 65years Lenalidomide(R) +/- MP: MPR-R vs. MPR vs. MP Cycles (28-day) 1-9 Cycles 10+ MPR-R M: 0.18 mg/kg, days 1-4 P: 2 mg/kg, days 1-4 R: 10 mg/day po, days 1-21 RANDOMISATION Diseaseprogression Lenalidomide (25 mg/day) +/- dexamethasone LenalidomideContinued Tx 10 mg/day,days 1-21 MPR M: 0.18 mg/kg, days 1-4 P: 2 mg/kg, days 1-4 R: 10 mg/day po, days 1-21 Primary Comparison MPR-R vs. MP Placebo MP M: 0.18 mg/kg, days 1-4 P: 2 mg/kg, days 1-4 PBO: days 1-21 Secondary Comparison MPR-R vs. MPR Addition of MPR arm per EMEA advice Placebo Open-Label Extension/Follow-Up Phase Double-Blind Treatment Phase Stratified by age (≤ 75 vs. > 75 years) and stage (ISS 1,2 vs. 3) M, melphalan; P, prednisone; R, lenalidomide; PBO, placebo.

  22. 100 75 50 25 0 0 5 10 15 20 25 30 35 40 Response & PFS: MPR-R vs.MPvs.MPR %RR (%CR): 77(10) vs. 50(3) vs. 68(3) HR 0.49 P < .0000001 HR 0.40 P = .153 Time (months) Median follow-up 30 months Palumbo et al. N Engl J Med 2012; 366: 1759-69

  23. OS: MPR-Rvs. MPR vs.MP Median follow-up 30 months Palumbo et al. N Engl J Med 2012; 366: 1759-69

  24. AEs During Induction:MPR-R vs.MPvs.MPR DVT, deep vein thrombosis; SMP: Second primary malignancy; AML, acute myelogenous leukemia; MDS, myelodysplastic syndrome Palumbo et al. N Engl J Med 2012; 366: 1759-69

  25. BORTEZOMIB

  26. VISTA: Bortezomib (V) as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone • Patients: Symptomatic multiple myeloma/end organ damage with measurable disease • ≥ 65 years or < 65 years and not transplant-eligible; KPS ≥ 60% VMP Cycles 1–4 Bortezomib 1.3 mg/m2 IV, d 1,4,8,11,22,25,29,32 Melphalan 9 mg/m2 IV, and prednisone 60 mg/m2 IV, d 1–4 Cycles 5–9 Bortezomib 1.3 mg/m2 IV, d 1,8,22,29 Melphalan 9 mg/m2 IVand prednisone 60 mg/m2 IV, d 1–4 R A N D O M I Z E • Primary end point: TTP • Secondary end points: CR rate, ORR, time to response, DOR, time to next therapy, OS, PFS, QoL (PRO) 9 x 6-week cycles (54 weeks) in both arms MP Cycles 1–9 Melphalan 9 mg/m2 IV and prednisone 60 mg/m2 IV, d 1–4 • Stratification: β2-microglobulin, albumin, region

  27. Bortezomib+MP (VMP) vs. MP: Efficacy Data(682 patients) 100 80 60 40 20 0 ORR: VMP 71%, MP 35%, CR: VMP 30%, MP 4% Time to progression Overall survival 52% reduced risk of progression on VMP ~36% reduced risk of death on VMP VMP MP 100 VMP MP 80 60 Patients without event (%) Patients without event (%) 40 Median follow-up 36.7 months 3-year OS: VMP: 69% MP: 54%, P=0.0008 20 VMP: 24.0 months MP: 16.6 months, P<0.000001 0 0 3 6 9 12 15 18 21 24 27 0 4 8 12 16 20 24 28 32 36 40 Time (months) Time (months) San Miguel et al. N Engl J Med 2008;359:906–917; Updated by Mateos et al JCO 2010

  28. OS (ITT)31% reduced risk of death with VMP Median OS benefit: 13.3 months 5-year OS rates: 46.0% vs 34.4% 100 90 80 70 60 50 40 30 20 10 0 Patients alive (%) Group N Event Median HR (95% CI) P-value MP 338 211 43.1 VMP 344 176 56.4 0.695 (0.567, 0.852) 0.0004 0 6 12 18 24 30 36 42 48 54 60 66 72 78 Time (months) Number of patients at risk: 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 San Miguel et al. ASH 2011; abstract 476

  29. Grade 3/4 Adverse Events San Miguel et al. ASH 2011; abstract 476 1Howlader N, et al. SEER Cancer Statistics Review, 1975-2008. http://seer.cancer.gov/csr/1975_2008/browse_csr.php?section=2&page=sect_02_table.07.html

  30. Progress in the Treatment of Elderly Patients with MM Novel agents SHOULD be included: Evidence based: bortezomib, lenalidomide > thalidomide Generating promising data: lenalidomide, bortezomib, carfilzomib

  31. Treatment of Elderly MM Patients Leading Questions • What is the goal of treatment (does CR matter)? • What is the best induction treatment? • Is it possible to individualize the treatment? • Can novel drugs improve outcome

  32. 8% if fully independent 14% if dependent in IADL 27% if dependent in ADL 40% if institutionalized 2-Year Mortality Rate for Persons Age 70 Years and Older Reuben. Am J Med. 1992;93:663.

  33. Comorbidity is a Key Factor in Survival Age-Comorbidity Score Actual 10-Year Survival (%) N Charlson et al. J Chronic Dis. 1987;40:373.

  34. Functional Assessment

  35. UPFRONT Protocol Induction: 21-day cycles Maintenance: 35-day cycles Cycles 1–4 Cycles 5–8 Cycles 9–13 VcDVc: 1.3 mg/m2, days 1,4,8,11D: 20 mg, days 1,2,4,5,8,9,11,12 Vc: 1.3 mg/m2, days 1,4,8,11D: 20 mg, days 1,2,4,5 Vc: 1.6 mg/m2, days 1,8,15,22 Rest period:days 23–35 VcTDVc: 1.3 mg/m2, days 1,4,8,11T: 100 mg, days 1–21 D: 20 mg, days 1,2,4,5,8,9,11,12 Vc: 1.3 mg/m2, days 1,4,8,11T: 100 mg, days 1–21 D: 20 mg, days 1,2,4,5 RANDOMIZE 1:1:1 VcMPVc: 1.3 mg/m2, days 1,4,8,11M: 9 mg/m2, days 1,2,3,4 of every other cycle P: 60 mg/m2, days 1,2,3,4 of every other cycle POSTER presentation ASH: 2013

  36. Patient Demographics andBaseline Disease Characteristics

  37. VcD (N=167, 40% PFS events) VcTD (N=168, 29% PFS events) VcMP (N=167, 36% PFS events) PFS (ITT population N=502) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Proportion of patients 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Time (Months) VD: 168 144 123 95 79 68 50 34 25 20 17 15 9 7 2 – – – VTD: 167 134 117 84 71 59 45 32 23 17 13 12 6 4 – 2 – – VMP:167 145 125 102 81 69 57 39 32 21 16 11 6 3 1 – – – Patients remaining, n • Median follow up was 13.4 months for the entire study population • Median PFS was 13.8, 18.4, and 17.3 months for the VcD, VcTD and VcMP arms, respectively • None of the pair-wise comparisons are statistically significant

  38. Induction Maintenance 58 56 54 52 50 Score 48 46 44 42 VD VTD VMP 40 Baseline Cycle 3 Day 1 Cycle 5 Day 1 Cycle 7 Day 1 Cycle 9 Day 1 Cycle 11 Day 1 Cycle 13 Day 1 Timepoint Patient-reported QoL(mean global health status score by treatment arm) • In all three treatment arms, there was a trend for decreasing QoL during induction, followed by an improvement/stabilization in QoL during maintenance • There was a trend for poorer QoL in the VTD vs. VD and VMP arms UPFRONT QoL poster (Niesvizky et al., ASH 2011, abstract 1864)

  39. Once-weekly Administration of Bortezomib as a Strategy to Improve Tolerability †Discontinuations due to SAEs 1. San Miguel et al. NEJM 2008;359:906 2. San Miguel et al. NEJM 2008;359:906; Supplementary Appendix 3. Mateos et al. J Clin Oncol 2010;28:2259-66 4. Palumbo et al.JCO 2010; 28:5101-09 5. Mateos et al. Lancet Oncol 2010;11:934-41

  40. Once-weekly Administration of Bortezomib as a Strategy to Maintain/Improve the Ffficacy 1. San Miguel et al. NEJM 2008;359:906 2. San Miguel et al. NEJM 2008;359:906; Supplementary Appendix 3. Mateos et al. J Clin Oncol 2010;28:2259-66 4. Palumbo et al. J Clin Oncol 2010;28:5101-9 5. Mateos et al. Lancet Oncol 2010;11:934-41

  41. Once-weekly Administration of Bortezomib as a Strategy to Improve Tolerability Mateos et al. IMW 2011: abstract 175

  42. Bortezomib IV versus SC 222 relapsed and/or refractory MM patients. Bz is given at conventional dose and scheme P=0·04 and 0·03 Moreau et al. Lancet Oncology 2011; 12(5): 431-40 Arnulf B et al. Haematologica 2012: Epub ahead of print No diferences in pharmakokinetics studies

  43. Treatment of Elderly MM Patients Leading Questions • What is the goal of treatment (does CR matter)? • What is the best induction treatment? • Is it possible to individualize the treatment? • Can novel drugs improve outcome

  44. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma Jakubowiak, et al Blood, 2013 CR 42% >VGPR 62%

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