Mieloma Múltiplo Tratamento do idoso

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

5 year survival rate (%) in multiple myeloma 24.6% 25.9% 27.6% 29.2% 32.3% 35.5% 44.9% 1975-1977 1978-1980 1981-1983 1990-1992 1996-1998 1999-2001 2003-2009 h-p://seer.cancer.gov/archive/csr/1975_2011/results_merged/sect_18_myeloma.pdf

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 50 45 40 35 30 25 20 15 10 5 0 1984 1986 1987 1989 1990 1992 1993 1995 1996 1998 Mieloma Múltiplo 1999 2001 2002 2004 <50 50 59 60 69 70 79 80+ Calendar period Brenner et al. Blood 2008;111:2521 26

Outcome of Myeloma Patients Mieloma Múltiplo Follow-up from diagnosis (years) 5-yr Survival (%) 2001 2005 2006 2010 P Overall 48 66 > 65 years 31 56.001 < 65 years 63 73 NS Kumar, Blood 2008

Mieloma Múltiplo MM Therapy: Therapeutic Options in the USA Standard of Care Therapies FDA Approvals in MM 1960 1970 1980 1990 2000 2010 ixazomib Daratumumab Elotozumab daratumumab 2015 2015 Ixazomib 1958 Melphalan 1983 Autologous Transplantation 2003 Bortezomib Panobinostat 2014 2013 Pomalidomide 1962 Prednisone 1969 Melphalan + Prednisone 2006 Thalidomide 2007 Doxil 2006 Lenalidomide 2012 Carfilzomib Adapted from Kumar SK et al. Blood. 2008;111:2516 2520.

Mieloma Múltiplo BRASIL Standard of Care Therapies 1960 1970 1980 1990 2000 2010 2016 1958 Melphalan 1983 Autologous Transplantation 2003 Bortezomib 1962 Prednisone 1969 Melphalan + Prednisone 2006 Thalidomide 2007 Doxil Carfilzomib Adapted from Kumar SK et al. Blood. 2008;111:2516 2520.

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

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

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): 1239-47 San Miguel. N Engl J Med 2008;359:906-17 San Miguel. J Clin Oncol. 2013; 31: 448-55 Facon T. ASH 2013: abstract number 2

Multiple Myeloma MELFALANO + PREDNISONA +TALIDOMIDA

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

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 100-200mg/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 100-200mg/ 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 95:271-278, 2016

. Multiple Myeloma Efficacy endpoint MPT n=32 CTD n=32 P value (MPT vs CTD) Response to treatment, % Complete/very good partial/ 14.3/25.0/28.6 20.7/34.5/34.5 partial response Stable disease/progressive 21.4/10.7 10.3/0 disease Overall response rate 67.9 89.7 0.056 Event-free survival Median, months 13.2 15.8 Hazard ratio* 1.05 0.847 Progression-free survival Median, months 24.1 25.9 Hazard ratio* 0.89 0.698 Overall survival Median, months 42.0 32.4 Hazard ratio* 1.08 0.821

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

Multiple Myeloma MELFALANO + PREDNISONA +BORTEZOMIBE

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 2007. Abstract 76.

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 < 10-10 ) ü Response duration in patients with CR: 24.0 vs 12.8 mos Response to Treatment (%) 100 80 60 40 20 0 P <.000001 82 50 ORR (CR + PR) P <.000001 46 35 5 CR (IF-) PR VMP (n = 336) MP (n = 331) 45 10 5 VGPR San Miguel JF, et al. ASH 2007. Abstract 76.

Bortezomib + MP (VMP) vs MP 682 patients Multiple Myeloma San-Miguel JF, et al. N Engl J Med. 2008;359(9):906-917; San Miguel JF, et al. J Clin Oncol. 2013;31(4):448-455

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

Multiple Myeloma FIRST trial: PFS Continuous Rd reduced the risk of disease progression by 28% vs. MPT Patients (%) 100 80 60 40 Rd (n= 535) Rd18 (n= 541) MPT (n= 547) Hazard ratio Rd vs. MPT: 0.72; P = 0.0006 Rd vs. Rd18: 0.70; P = 0.0001 Rd18 vs. MPT: 1.03; P = 0.70349 Median PFS 25.5 mos 20.7 mos 21.2 mos 20 0 72 wks 0 6 12 18 24 30 36 42 48 54 60 Time (months) Rd 535 400 319 265 218 168 105 55 19 2 0 Rd18 541 391 319 265 167 108 56 30 7 2 0 MPT 547 380 304 244 170 116 58 28 6 1 0 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.

Facon T, et al. Blood. 2013;122:abstract 2. Multiple Myeloma FIRST trial: OS interim analysis (574 deaths. 34%) 100 80 4-year OS Rd (n= 535) 59.4% Rd18 (n= 541) 55.7% MPT (n= 547) 51.4% Patients (%) 60 40 20 0 Hazard ratio Rd vs. MPT: 0.78; P = 0.017 (È 22% risk of death with Rd) Rd vs. Rd18: 0.90; P = 0.307 Rd18 vs. MPT: 0.88; P = 0.184 0 6 12 18 24 30 36 42 48 54 60 Overall survival (months) Rd Rd18 MPT 535 541 547 488 505 484 457 465 448 433 425 418 403 393 375 338 324 312 224 209 205 121 124 106 43 44 30 5 6 3 0 0 0

Multiple Myeloma TRATAMENTO Equilibrar eficácia vs toxicidade

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 (%) 1.00 0.00 0.25 0.50 0.75 < 75 years > 75 years 3-year OS 68% 57% 0 0.5 1 1.5 2 2.0 3 Time since diagnosis (years) Age < 75 years Age > 75 years Bringhen et al, Hematologica 2013

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 1.00 1.00 Probability of survival (%) 0.75 0.50 0.25 0.00 No grade 3 to4 non-hematological Aes Grade 3 to 4 non-hematological AEs Probability of survival (%) 0.75 0.50 0.25 0.00 No discontinuation due to AEs Drug discontinuation due to AEs 0 0.5 1 1.5 2 2.0 3 0 0.5 1 1.5 2 2.0 3 Time since diagnosis (years) Time since diagnosis (years) Bringhen et al, Hematologica 2013

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

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

Multiple Myeloma Age-Adjusted Therapy INCIDENCE: 2002 8.9/100.000 Full-dose chemotherapy Autologous transplant 65-74 years 25-64 years 36% 31% 33% 75-101 years Reduced-dose chemotherapy Regione Piemonte, Assessorato Sanità 2006

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

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

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 (31.3 97.9) 55 (25.9 73.1) 60.9 (25.9-97.9) 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%)

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%)

Multiple Myeloma Overall survival of transplantation-ineligible 100 80 OS median=43 months 38% at 5 years 60 40 20 0 0 20 40 60 80 100 Time Number at risk 441 227 129 73 16 0

Outcome of Myeloma Patients Mieloma Múltiplo Follow-up from diagnosis (years) 5-yr Survival (%) 2001 2005 2006 2010 P Overall 48 66 > 65 years 31 56.001 < 65 years 63 73 NS Kumar, Blood 2008

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

Multiple Myeloma OBRIGADA!!! hungria@dialdata.com.br