Mieloma Múltiplo Tratamento do idoso

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1 Mieloma Múltiplo Mieloma Múltiplo Tratamento do idoso Prof. Dra. Vania Tietsche de Moraes Hungria Professora Adjunta da Disciplina de Hematologia e Oncologia da Faculdade de Ciências Médicas da Santa Casa de São Paulo

2 5 year survival rate (%) in multiple myeloma 24.6% 25.9% 27.6% 29.2% 32.3% 35.5% 44.9% h-p://seer.cancer.gov/archive/csr/1975_2011/results_merged/sect_18_myeloma.pdf

3 Improvements in survival according to the age 10-year relative survival (%) Period estimates of 10-yr survival by major age groups in defined calendar periods Mieloma Múltiplo < Calendar period Brenner et al. Blood 2008;111:

4 Outcome of Myeloma Patients Mieloma Múltiplo Follow-up from diagnosis (years) 5-yr Survival (%) P Overall > 65 years < 65 years NS Kumar, Blood 2008

Mieloma Múltiplo MM Therapy: Therapeutic Options in the USA Standard of Care

Daratumumab Elotozumab daratumumab 2015 2015 Ixazomib 1958 Melphalan 1983

Pomalidomide 1962 Prednisone 1969 Melphalan + Prednisone 2006 Thalidomide

5 Mieloma Múltiplo MM Therapy: Therapeutic Options in the USA Standard of Care Therapies FDA Approvals in MM ixazomib Daratumumab Elotozumab daratumumab Ixazomib 1958 Melphalan 1983 Autologous Transplantation 2003 Bortezomib Panobinostat Pomalidomide 1962 Prednisone 1969 Melphalan + Prednisone 2006 Thalidomide 2007 Doxil 2006 Lenalidomide 2012 Carfilzomib Adapted from Kumar SK et al. Blood. 2008;111:

Mieloma Múltiplo BRASIL Standard of Care

1958 Melphalan 1983 Autologous Transplantation

+ Prednisone 2006 Thalidomide 2007 Doxil

6 Mieloma Múltiplo BRASIL Standard of Care Therapies Melphalan 1983 Autologous Transplantation 2003 Bortezomib 1962 Prednisone 1969 Melphalan + Prednisone 2006 Thalidomide 2007 Doxil Carfilzomib Adapted from Kumar SK et al. Blood. 2008;111:

7 Tratamento individualizado Multiple Myeloma Estratificação Idade e PS (< ou > 65/70 anos) Fatores de risco Transplante / Não-transplante - Citogenética - ISS - Função Renal - DHL - Doença Extramedular Standard vs Alto risco

8 Multiple Myeloma Mieloma Múltiplo Recém diagnosticado Candidato ao transplante autólogo da medula óssea SIM NÃO

9 New standards of care of elderly MM pts Multiple Myeloma Alkylators-based regimens MP Alkylators-free regimens IMiD s MPT VMP Len-dex Six randomized trials: Benefit in PFS 6m OS... 6m One randomized trial: Benefit in PFS... 8m OS... 13m One randomized trial: Benefit in PFS & OS vs MPT Fayers PM et al. Blood 2011; 118(5): San Miguel. N Engl J Med 2008;359: San Miguel. J Clin Oncol. 2013; 31: Facon T. ASH 2013: abstract number 2

10 Multiple Myeloma MELFALANO + PREDNISONA +TALIDOMIDA

11 Multiple Myeloma MPT vs MP: Meta-analysis of 1685 individualpatient data from 6 randomized trials Fayers et al, Blood 2011

12 Multiple Myeloma Phase 3 trial of three thalidomide-containing regimens in patients with newly diagnosed multiple myeloma not transplant-eligible CTD (ciclofosfamida 50 mg/ dia, Talidomida mg/dia, dexa 40mg d1 a d4, d15 a d 18 ciclos 1 e 2 e d1 a d4 ciclos 3 a 9) MPT (melfalano 4mg/m 2 por 7 dias, prednisona 40mg/m 2 por 7 dias e talidomida mg/ dia) total de 9 ciclos TD (talidomida 100 a 200mg/dia, dexa 40mg d1 a d4, d9 a d12 ciclos ímpares e d1 a d4 ciclos pares) total de 9 ciclos GBRAM Ann Hematol 95: , 2016

13 . Multiple Myeloma Efficacy endpoint MPT n=32 CTD n=32 P value (MPT vs CTD) Response to treatment, % Complete/very good partial/ 14.3/25.0/ /34.5/34.5 partial response Stable disease/progressive 21.4/ /0 disease Overall response rate Event-free survival Median, months Hazard ratio* Progression-free survival Median, months Hazard ratio* Overall survival Median, months Hazard ratio*

14 Multiple Myeloma Conclusion CTD or MPT as suitable frontline regimens for patients with multiple myeloma who are not candidates to transplantation.

New standards of care of elderly MM pts Multiple Myeloma Alkylators-based regimens MP Alkylators-free regimens IMiD s MPT VMP Len-dex Six randomized trials: Benefit in PFS 6m OS.

15 New standards of care of elderly MM pts Multiple Myeloma Alkylators-based regimens MP Alkylators-free regimens IMiD s MPT VMP Len-dex Six randomized trials: Benefit in PFS 6m OS... 6m One randomized trial: Benefit in PFS... 8m OS... 13m One randomized trial: Benefit in PFS & OS vs MPT Fayers PM et al. Blood 2011; 118(5): San Miguel. N Engl J Med 2008;359: San Miguel. J Clin Oncol. 2013; 31: Facon T. ASH 2013: abstract number 2

16 Multiple Myeloma MELFALANO + PREDNISONA +BORTEZOMIBE

17 Mieloma Múltiplo VMP vs MP in Newly Diagnosed MM (MMY-3002; VISTA) 54 weeks Patients 65 years of age or older or not transplant eligible with untreated MM (N = 682) Bortezomib IV 1.3 mg/m 2 on Days 1, 4, 8, 11, 22, 25, 29, 32 for four 6-week cycles + Melphalan and Prednisone* (n = 344) Bortezomib IV 1.3 mg/m 2 on Days 1, 8, 22, 29 for five 6-week cycles + Melphalan and Prednisone* (n = 344) Melphalan and Prednisone* for nine 6-wk cycles (n = 338) *Melphalan PO 9 mg/m2 once daily and prednisone 60 mg/m2 on Days 1-4 each cycle. San Miguel JF, et al. ASH Abstract 76.

18 Mieloma Múltiplo VMP vs MP in Newly Diagnosed MM (MMY-3002; VISTA): Response to Treatment Responses with VMP rapid and durable ü Time to response, all responders: 1.4 vs 4.2 mos (P < ) ü Response duration in patients with CR: 24.0 vs 12.8 mos Response to Treatment (%) P < ORR (CR + PR) P < CR (IF-) PR VMP (n = 336) MP (n = 331) VGPR San Miguel JF, et al. ASH Abstract 76.

19 Bortezomib + MP (VMP) vs MP 682 patients Multiple Myeloma San-Miguel JF, et al. N Engl J Med. 2008;359(9): ; San Miguel JF, et al. J Clin Oncol. 2013;31(4):

20 New standards of care of elderly MM pts Multiple Myeloma Alkylators-based regimens MP Alkylators-free regimens IMiD s MPT VMP Len-dex Six randomized trials: Benefit in PFS 6m OS... 6m One randomized trial: Benefit in PFS... 8m OS... 13m One randomized trial: Benefit in PFS & OS vs MPT Fayers PM et al. Blood 2011; 118(5): San Miguel. N Engl J Med 2008;359: San Miguel. J Clin Oncol. 2013; 31: Facon T. ASH 2013: abstract number 2

FIRST: Phase 3 trial of Lenalidomide + low-dose Dex vs MPT (IFM 07-01; MM-020) Multiple Myeloma N = 1,623 Previously untreated MM Age 65 years or not eligible for a transplant No

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.

21 FIRST: Phase 3 trial of Lenalidomide + low-dose Dex vs MPT (IFM 07-01; MM-020) Multiple Myeloma N = 1,623 Previously untreated MM Age 65 years or not eligible for a transplant No neuropathy of grade > 2 R A N D O MI ZA TI O N Rd (28-day cycle; until disease progression) Lenalidomide 25 mg/day, days 1 21 Dexamethasone* 40 mg/day, days 1, 8, 15, and 22 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 4 Prednisone 2.0 mg/kg/day, days 1 4 Thalidomide* 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 Facon et al. ASH 2013: abstract 2

22 Multiple Myeloma FIRST trial: PFS Continuous Rd reduced the risk of disease progression by 28% vs. MPT Patients (%) Rd (n= 535) Rd18 (n= 541) MPT (n= 547) Hazard ratio Rd vs. MPT: 0.72; P = Rd vs. Rd18: 0.70; P = Rd18 vs. MPT: 1.03; P = Median PFS 25.5 mos 20.7 mos 21.2 mos wks Time (months) Rd Rd MPT mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, Lenalidomide plus low-dose dexamethasone. Facon T, et al. Blood. 2013;122:abstract 2.

23 Facon T, et al. Blood. 2013;122:abstract 2. Multiple Myeloma FIRST trial: OS interim analysis (574 deaths. 34%) year OS Rd (n= 535) 59.4% Rd18 (n= 541) 55.7% MPT (n= 547) 51.4% Patients (%) Hazard ratio Rd vs. MPT: 0.78; P = (È 22% risk of death with Rd) Rd vs. Rd18: 0.90; P = Rd18 vs. MPT: 0.88; P = Overall survival (months) Rd Rd18 MPT

24 Multiple Myeloma TRATAMENTO Equilibrar eficácia vs toxicidade

25 Negative impact of age on survival Meta-analysis of European trials (MP vs MPT, VMP vs VTP, VMP vs VMPT-VT) 1435 newly diagnoses MM Multiple Myeloma Probability of survival (%) < 75 years > 75 years 3-year OS 68% 57% Time since diagnosis (years) Age < 75 years Age > 75 years Bringhen et al, Hematologica 2013

26 Multiple Myeloma Negative impact of grade 3-4 non-haematological toxicity and discontinuation due to adverse events Meta-analysis of European trials (MP vs MPT, VMP vs VTP, VMP vs VMPT-VT) 1435 newly diagnoses MM Probability of survival (%) No grade 3 to4 non-hematological Aes Grade 3 to 4 non-hematological AEs Probability of survival (%) No discontinuation due to AEs Drug discontinuation due to AEs Time since diagnosis (years) Time since diagnosis (years) Bringhen et al, Hematologica 2013

27 Multiple Myeloma Framework for the definition of frailty status in elderly patients with myeloma ADL, Activity of Daily Living; CCI, Charlson comorbidity index; IADL, Instrumental Activity of Daily Living

28 Multiple Myeloma Treatment algorithm for elderly patients with myeloma Unfit Frail Conditions

29 Multiple Myeloma Age-Adjusted Therapy INCIDENCE: / Full-dose chemotherapy Autologous transplant years years 36% 31% 33% years Reduced-dose chemotherapy Regione Piemonte, Assessorato Sanità 2006

30 Multiple Myeloma MULTIPLE MYELOMA PROFILE IN LATIN AMERICA: A WEB-BASED CLINICAL AND EPIDEMIOLOGICAL OBSERVATIONAL STUDY Prospective Study Annals of Hematology 2016

31 Multiple Myeloma Methods and Characteristics Prospective study 17 centers in Brazil, Mexico 2, Chile 1, Peru 1, Argentina 1 Diagnosed between 1/01/2005 and 31/12/2007 follow-up until 31/12/2012 N = 852 patients Data of this patients: ü Age ü Sex ü Race ü Monoclonal component type ü Creatinine ü Hypercalcemia ü Presence of anemia ü Lytic lesions ü Durie & Salmon Staging ü International Staging System ü Treatment

32 Patients characteristics (median follow-up 62 months) Characteristic Transplantation-ineligible Transplantation-eligible All patients patients patients Value or N (%) Value or N (%) Value or N (%) Age N=460 N=390 N=850 Median (range), years 68.6 ( ) 55 ( ) 60.9 ( ) Mean (standard deviation), years 67.4 (11.2) 54.7 (8.2) 61.6 (11.8) Sex N=461 N=391 N=852 Female 233 (50.5) 167 (42.7) 400 (46.9%) Male 228 (49.5) 224 (57.3) 452 (53.1%) Monoclonal component N=420 N=376 N=796 IgG 246 (58.6) 203 (54.0) 449 (56.4%) IgA 102 (24.3) 85 (22.6) 187 (23.5%) IgM 5 (1.2) 2 (0.5) 7 (0.9%) Light chain only 56 (13.3) 75 (19.9) 131 (16.5%) Non-secretory 11 (2.6) 11(2.9) 22 (2.8%) Bone lesions N=436 N=372 N=808 Absent 61 (14.0) 33 (8.9) 94 (11.6%) Present 375 (86.0) 339 (91.1) 714 (88.4%)

33 Patients characteristics (median follow-up 62 months) Durie-Salmon stage N=434 N=377 N=811 I 61 (14.1) 16 (4.2) 77 (9.5%) II 84 (19.3) 91 (24.1) 175 (21.6%) III 289 (66.6) 270 (71.6) 559 (68.9%) International Staging System stage N=380 N=333 N=713 I 101 (26.6) 108 (32.4) 209 (29.3%) II 135 (35.5) 125 (37.5) 260 (36.5%) III 144 (37.9) 100 (30.0) 244 (34.2%) Creatinine N=459 N=374 N=833 2 mg/dl 336 (73.2) 291 (77.8) 627 (75.3%) >2 mg/dl 123 (26.8) 83 (22.2) 206 (24.7%) Hypercalcemia N=428 N=356 N=784 Absent 327 (76.4) 268 (75.3) 595 (75.9%) Present 101 (23.6) 88 (24.7) 189 (24.1%)

34 Multiple Myeloma Overall survival of transplantation-ineligible OS median=43 months 38% at 5 years Time Number at risk

35 Outcome of Myeloma Patients Mieloma Múltiplo Follow-up from diagnosis (years) 5-yr Survival (%) P Overall > 65 years < 65 years NS Kumar, Blood 2008

36 Multiple Myeloma Conclusões Vários esquemas podem ser considerados como standard para os pacientes não elegíveis ao TMO Esquemas baseados em agentes alquilantes mais utilizados: VMP ou MPT ou CTD ü MP+agente novo ü Aumento na SLP ü Impacto na SG Esquema não baseado em agentes alquilantes: Rd (lenalidomida+dexametasona) contínuo é superior a MPT Papel da manutenção não está esclarecido até o momento As doses devem ser modificadas de acordo com a idade e comorbidades

37 Multiple Myeloma OBRIGADA!!!

Multiple Myeloma Highlights From the 2015 ASCO Annual Meeting and the 20 th Congress of EHA

Multiple Myeloma Highlights From the 2015 ASCO Annual Meeting and the 20 th Congress of EHA July 13, 2015 Welcome and Introductions Anne Quinn Young, MPH Multiple Myeloma Research Foundation Norwalk, CT