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Heinz Ludwig Department of Medicine I Center for Oncology, Hematology and Palliative Care

Heinz Ludwig Department of Medicine I Center for Oncology, Hematology and Palliative Care Wilhelminenhospital, Vienna, Austria. What we know about myeloma in elderly patients from trials and observational studies?. Goals of therapy in elderly patients. Drug combinations for elderly patients.

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Heinz Ludwig Department of Medicine I Center for Oncology, Hematology and Palliative Care

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  1. Heinz Ludwig Department of Medicine I Center for Oncology, Hematology and Palliative Care Wilhelminenhospital, Vienna, Austria What we know about myeloma in elderly patients from trials and observational studies?

  2. Goals of therapy in elderly patients

  3. Drug combinations for elderly patients Possible options *only exceptional cases Most commonly used combinations contain 2-3 drugs

  4. Characteristics of the Elderly PatientChronological age does not necessarily correlate with biological age • All three individuals are 70 years old • Fit Minor morbidity significant morbidity The variation in biological fitness in a specific age cohort increases with rising age, but the ‚biology‘ of myeloma cells does not vary with age

  5. Treatment of patients with multiple myeloma not eligible for transplantation • Assess fraility Fit Unfit Frail Full go Slow go Very slow go 2 or 3 drug regimen reduce dose 2 (3) drug regimen further dose reduction MP, CTX-P VD, Ld

  6. Instruments for assessing fraility and allocation to treatment groups • Assess • Age • ADL • IADL • Charlson • comorbidity • score Palumbo A et al. IMW 2013

  7. Adaptation of dose according to risk factors • Palumbo et al.,BLOOD 2011

  8. Comorbidities relevant for treatment selection in myeloma

  9. Higher risk of mortality in patients ≥ 75 years of age Retrospective meta-analysis of 4 EU phase III trials (N = 1,435) with MP, MPT, VMP, and VMPT • Median follow up 33 months • Median OS in total population 50 months • Estimated 3-year OS 68% in patients < 75 years of age vs 57% in patients ≥ 75 years of age (HR 1.44, CI 1.20-1.72, p < 0.001) 0.1 1 10 Higher mortality in patients < 75 years of age Higher mortality in patients ≥ 75 years of age Bringhen S, et al. Haematologica. 2013;98:980-7.

  10. Age and Organ Damage Correlate with Poor OS: Meta-analysis of 4 Randomized Trials • n=1435 (≥ 65 yrs ): MPT vs MP, VMP vs MP, VMP vs VMPT-VT Bringhen et al. Haematologica 2013;98(6):980-987

  11. Phase III studies incorporating novel agents in the non-transplant setting • *Meta-analysis of the 6 trials:  PFS () OS

  12. PFS HR=0.67 in favor of MPT, p<0.0001 1.0 MPT MP 0.8 Median 20.3 mos (18.8-21.6) 0.6 Survival proportion HR=0.83 in favor of MPT, p=0.005* 0.4 1.0 Median 14.9 mos (14.0-16.6) 0.2 Median 39.3 mos (35.6-44.6) 0.8 0.0 0 12 24 36 48 0.6 months Median 32.7 mos (30.5-36.6) 0.4 0.2 0.0 0 12 24 36 48 months MPT vs MP: Meta-analysis of 1685 individual-patient data of 6 randomized trials OS MPT MP *Cox model for treatment, with analysis stratified by study using a random effects (frailty) model Fayers et al. Blood 2011, accepted for publication 30 May 2011

  13. MPT: Pros and Cons Pros • Survival benefit • Oral regimen • Not expensive Cons • Thalidomide toxicity • Suboptimal in cytogenetic high risk group • Shorter survival after relapse

  14. MP vs. VMP (VISTA) Final updated OS analysis 100 90 80 70 60 50 40 30 20 10 0 Median OS benefit: 13.3 months 5-year OS rates: 46.0% vs 34.4% Patients alive (%) Group N Event Median HR (95% CI) P-value M 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) Median follow-up 60.1 months 31% reduced risk of death San Miguel et al. JCO 2013

  15. Overall survival in different subgroups: VMP vs. MP San Miguel et al., JCO 2013

  16. VMP induced CR is associated with improved outcome Time to progression Time to next therapy Overall survival Treatment-free interval Harousseau JL et al., BLOOD 2010

  17. VD vs. VTD vs. VMP followed by bortezomib maintenance therapy Niesvitzky R. et al., BLOO, 116 2010

  18. Global QoL during VD, VTD and VMP induction therapy VD vs. VTD or VMP: shorter PFS, similar OS, better tolerance Niesvizky R et al., ASH 2011

  19. Treatment schedule

  20. PFS and OS: VMP vs VMPT –VT Progression free survival Overall survival landmark analysis Palumbo A et al. ASH 2012

  21. Overall survival, Landmark analysis

  22. Overall survival from relapse Palumbo et al. ASH 2012 (Abstract 200)

  23. VMPT-VT versus VMP in newly diagnosed elderly patients • Significant OS benefit in patients • < 75 years of age (none in pts > 75 years) • With stage ISS 1-2 (tendency for  OS in stage ISS 3) • With CR (none in pts with VGPR/PR) • Benefit in ‚good risk‘ patients with CR only • Grade 3- 4 adverse events during VT maintenance • PN 7% • Hematological toxicity 5% • Infection 3% • Discontinuation due to AEs 12% Palumbo et al. ASH 2012 (Abstract 200), oral presentation

  24. How to reduce toxicity of Bortezomib and and maintain efficacy? • Bortezomib once weekly • longer duration of therapy • similar cumulative dose • similar efficacy • less toxicty (G3/4 neurotoxicity) • Bortezomib subcutaneously • 10 times lower serum peak concentration • similar area under the curve • less neurotoxicity • similar efficacy

  25. - N = 459, 82 centers in Europe, Australia, and Israel Open - Label Double-blind Treatment Phase Extension Phase Cycles (28 - day) 1 - 9 Cycles 10+ MPR - R Maintenance M: 0.18 mg/kg, days 1 - 4 P: 2 mg/kg, days 1 - 4 Lenalidomide 10 mg/day R: 10 mg/day po , days 1 - 21 days 1 - 21 MPR Lenalidomide RANDOMIZATION M: 0.18 mg/kg, days 1 - 4 Disease (25 mg/day) P: 2 mg/kg, days 1 - 4 Placebo Progression +/ - Dexamethasone R: 10 mg/day po , days 1 - 21 MP M: 0.18 mg/kg, days 1 - 4 P: 2 mg/kg, days 1 - 4 Placebo PBO: days 1 - 21 • Stratified by age (<75 years vs > 75 years) and stage (ISS I/II vs III) • - ISS, International Staging System; MP, melphalan , prednisone; MPR, melphalan , prednisone, lenalidomide ; MPR - R, melphalan , prednisone, lenalidomide with lenalidomide maintenance; PBO, placebo. • MPR-R vs. MPR vs. MP (MM015 trial)

  26. Progression - Free and Overall Survival All Patients Median PFS Median PFS 4 4 - - year OS year OS MPR MPR - - R R 59% 59% MPR MPR - - R R 31 months 31 months MPR MPR 58% 58% MPR MPR 14 months 14 months MP MP 58% 58% 100 MP MP 13 months 13 months 100 HR 0.898 75 75 .579 P = Patients (%) HR 0.395 Patients (%) 50 50 < .001 P HR 1.089 = .648 P HR 0.796 25 25 = .135 P 0 0 0 10 20 30 40 40 50 20 30 60 10 0 Time (Months) Time (Months) TTP HR advantages were similar: MPR - R vs MP = 0.337; MPR vs MP = 0.826 • HR, hazard ratio; MP, melphalan , prednisone; MPR, melphalan , prednisone, lenalidomide ; MPR - R, melphalan , prednisone, lenalidomide with lenalidomide maintenance; OS, overall survival; PFS, progression - free survival; TTP, time to progression. • Progression-free and overall survival

  27. PFS and OS with MPR-R and MPR patients aged 65-75 years

  28. FIRST: Phase 3 trial of Lenalidomide + low-dose Dex vs MPT (IFM 07-01; MM-020) Centres in EU, Switzerland, APAC, USA, and Canada Rd (28-day cycle; until disease progression) Lenalidomide 25 mg/day, days 1–21 Dexamethasone* 40 mg/day, days 1, 8, 15, and 22 RANDOMIZATION • Inclusion criteria • N = 1,623 • Previously untreated MM • Age  65 years or not eligible for a transplant • No neuropathy of grade > 2 Rd (28-day cycle; up to 18 cycles) Lenalidomide 25 mg/day, days 1–21 Dexamethasone* 40 mg/day, days 1, 8, 15, and 22 MPT (6-week cycle; up to 12 cycles ) Melphalan* 0.25 mg/kg/day, days 1–4Prednisone 2.0 mg/kg/day, days 1–4Thalidomide* 200 mg/day Primary end-point: PFS *In patients aged > 75 years: Dex 20 mg/day, melphalan 0.20 mg/kg/day, thalidomide 100 mg/day NCT00689936. Available from: www.clinicaltrials.gov.

  29. What is the optimal duration of first line therapy? Duration of therapy: minimally 6, maximally 12 months Most experts recommend ≈ 9 months

  30. Outcome with novel combinations 1MTCG. J Clin Oncol 1998;16(12):3832-42 2Ludwig et al., BLOOD 2009 2Pönisch et al. J Cancer Res Clin Oncol. 2006;132:205-12. 3Fayers et al. Blood 2011; 118(5):1239-1247 4Morgan et al. Blood 2011;118:1231-8 5San Miguel et al. JCO 2013; 31(4): 448-455 6Palumbo et al. N Engl J Med 2012;366(19):1759-69 7Mateos et al. Blood 2012; 120: 2581-2588 8Palumbo et al. ASH 2012 (Abstract 200), oral presentation 9Palumbo et al. ASH 2011 (Abstract 653), oral presentation 10Facon et al. ASH 2013 (Abstract 2), oral presentation

  31. Hematologic CR correlates with long 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 VGPR Probability Probability PR PR P<0.001 P<0.001 Gay et al. Blood 2011; 117(11):3025-31

  32. Immunophenotypc CR correlates with OS GEM2005 >65y 100 PFS Immunophenotypic CR 90% at 3y “Stringent CR” 38% at 3y Conventional CR 57% at 3y PR (≥70% reduction) 28% at 3y 80 60 40 20 Paiva et al; J Clin Oncol. 2011;29(12):1627-33.

  33. 1.00 1.00 del(17p) < 60 del(17p) ≥ 60 t(4:14) neg t(4:14) pos 0.75 0.75 0.50 0.50 0.25 0.25 0.00 0.00 0 0 1 1 2 2 3 3 4 4 5 5 Cytogeneticabnormalities are a major prognosticfactor in elderly patients with MM: IFM experience 1,890 patients (median age 72, range 66–94), including 1,095 patients with updated data on treatment modalities and survival OS according to t(4:14) OS according to del(17p) p < 10.4 p < 10.6 Probability of OS Probability of OS Time (years) Time (years) • Whatever the treatment, t(4;14) and del(17p) were associated with shorter PFS and OS; similar results were achieved in the subgroup of 335 patients > 75 years 1. Avet-Loiseau H, et al. J Clin Oncol. 2013 31(22):2806-9. 2. Hulin et al. Blood 2012:[abstract 204].

  34. The challenge of high-risk CA [t(4;14), del(17p), t(14;16)] in NDMM elderly patients First generation novel agents only partly overcome the negative prognosis of high-risk CA in newly diagnosed elderly patients with MM 1. Bergsagel PL, et al. Blood. 2013;121:884-91. 2. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. 3. San Miguel J, et al. J Clin Oncol. 2013;31:448-55. 4. Mateos MV, et al. Blood. 2011;118:4547-53.

  35. Maintenance studies - summary

  36. Summary: Treatment results in elderlypatients • MPT,  PFS, +/- OS, can be toxic in elderly pts • VMP,  PFS  OS, may induce severe PNP • Ld,  PFS,  OS, low dose Dex recommended • Thal-Dex, an option for fit pts • CTDa vs MP,  overall response rate,  CR, VGPR • Bendamustine-Pred, approved for first line TX • Thalidomide maintenance  PFS, but not OS • MPR with Lenalidomide maintenance PFS, but not OS • VT maintenance not significantly better than VP

  37. The natural course of multiple myeloma Maintenance

  38. Treatment of relapsed/refractory MMGeneral considerations Components of initial therapy Alkylating-based Dexamethasone-based IMiD-based Bortezomib-based Efficacy of initial therapy Quality of response Tolerance of tretament Duration of respose Patient status and type of relapse Age, performance status, glucose metabolism Aggressive vs non-aggressive relapse Bone marrow reserve Renal function impairment Pre-existing peripheral neuropathy Oral vs. iv therapy IMiD, immunomodulatory derivative; MM, multiple myeloma

  39. Treatment of Relapsed/Refractory Myeloma Frontline Therapy successful? YesNo Long duration of response Select other TX (Class switch) YesNo Repeat first line TX Select other TX Bortezomib based frontline TX: IMiD based frontline TX Pomalidomide • IMiD-based • TD • MPT • CTD • Rd • (MPR) Old Type MP DCEP M-100 + ASCT Bort-based VD VMP VTD Ludwig et al. The Oncologist 2011

  40. Retreatment with bortezomib: a meta-analysis including 23 studies • 23 trials, 1051 patients • Patients refractory or not refractory to bortezomib • 11 studies including bortezomib-refractory pts • 6 studies excluding bortezomib-refractory pts • 6 studies missing information on bortezomib-refractory pts • Combinations • Bortezomib ± Dex: 4 studies • Bortezomib + combination therapy: 19 studies Knopf et al. IMW 2013 (Abstract P-228), poster presentation

  41. Knopf et al., IMW 2013 Results of meta-analysis of retreatement with bortezomib in different risk groups

  42. Carfilzomib a second generation proteasome inhibitor

  43. Single agent Carfilzomib in relapsed/refractory patients Progressive disease at enrollment, Relapsed from 2 prior TX lines, Must include bortezomib Must include thalidomide or lenalidomide, Refractory to last line Siegel D et al., BLOOD 2012

  44. Pomalidomide + LoDex vs HiDex (MM-003): Phase III Trial Design • Primary endpoint: PFS • Secondary endpoints: OS, ORR, DOR, safety Stratified by age (≤ 75 vs > 75 yrs), number of previous treatments (2 vs > 2), disease population (refractory vs relapsed/refractory vs intolerant/refractory) 28-day cycles POM + LoDexPomalidomide 4 mg on Days 1-21 +Dexamethasone 40 mg (if ≤ 75 yrs) or 20 mg (if > 75 yrs) on Days 1, 8, 15, 22(n = 302) Follow-up for OS and SPM until 5 yrsPost enrollment Until PD* Patients with relapsed/refractory myeloma(N = 455) HiDexDexamethasone 40 mg (if ≤ 75 yrs) or 20 mg (if > 75 yrs) on Days 1-4, 9-12, 17-20 (n = 153) Companion trial MM-003C: Pomalidomide 21/28 days Until PD* *Independently adjudicated in real time. Thromboprophylaxis indicated for patients receiving pomalidomide or with history of DVT. San Miguel JF, et al. ASCO 2013. Abstract 8510.

  45. Pomalidomide + LoDex vs HiDex: Key Criteria for Pts With Relapsed/Refractory MM • All patients • Refractory to last therapy • ≥ 2 previous therapies • ≥ 2 consecutive cycles of lenalidomide and bortezomib (alone or in combination) or adequate previous alkylator therapy • Failed bortezomib and lenalidomide • Progression within 60 days; PR with progression within 6 mos, and/or bortezomib intolerant after ≥ 2 cycles and achieving ≤ MR • Refractory or relapsed/refractory • Primary refractory (never achieved better than PD to any therapy) or relapsed and refractory (relapsed after having ≥ SD for ≥ 2 cycles of therapy to ≥ 1 previous regimen and then developed PD ≤ 60 days of completing their last treatment) San Miguel JF, et al. ASCO 2013. Abstract 8510.

  46. Pomalidomide + LoDex vs HiDex (MM-003) PFS (ITT Population) OS (ITT Population) Mos Mos San Miguel JF, et al. ASCO 2013. Abstract 8510.

  47. Pomalidomide + LoDex vs HiDex Adverse Events (MM-003) *Includes hyperesthesia, peripheral sensory neuropathy, paraesthesia, hypoesthesia, and polyneuropathy. San Miguel JF, et al. ASCO 2013. Abstract 8510.

  48. Zoledronic Acid vs Clodronate in Newly Diagnosed MM: SREs HR: 0.74 (P = .0004) CLO 40 35.3% 30 27.0% Patients With an SRE (%) ZOL 20 10 0 0 18 24 30 36 42 6 12 Time From Randomization (Mos) Patients at Risk, n ZOL 981 663 506 390 284 201 138 97 CLO 979 629 465 337 256 173 112 74 *SREs defined as vertebral fractures, other fractures, spinal cord compression, and the requirement for radiation or surgery to bone lesions or the appearance of new osteolytic bone lesions. Morgan GJ, et al. ASH 2010. Abstract 311. • Significantly reduced incidence of SREs* with zoledronic acid vs clodronate • Regardless of presence of bone lesions at baseline

  49. Planned and/or ongoing studies VD vs VTD vs VMP + V maintenance (UPFRONT study) VRd vs Rd + Rd maintenance (SWOG S0777) Rd vs MPT vs Rd + Rd maintenance(MM20/IM(FIRST trial) Rd vs MPR vs CRP + maintenance R vs RP (EMNTG) MPT+T vs MPR+R (HOVON 87-NMSG 18, ECOG EA1A06) CTDa vs RCD +/- R maintenance (MRC Myeloma XI) VP vs VMP vs VCP + VP maintenance(EMNTG) Carfilzomib + MP (CARMYSAP trial): ORR of 92% (40% VGPR). EHA 2012 MLN9708 plus LD and MLN9708 plus MP:EHA 2012 Rd vs MEL140 (DSMM XIII) Pomalidomide + Dex vs Dexamethasone:MM 005 Alternating treatment with different regimens: VMP and RD (PETHEMA/GEM)Bortezomib + Bendamustine + Prednisone (PETHEMA/GEM)

  50. New drugs in clinical evaluation

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