mieloma múltiplo tratamento do idoso -...
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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
1975-‐1977 1978-‐1980 1981-‐1983 1990-‐1992 1996-‐1998 1999-‐2001 2003-‐2009
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
Mieloma Múltiplo
Improvements in survival according to the age
Period estimates of 10-yr survival by major age groups in defined calendar periods
Brenner et al. Blood 2008;111:2521–26
10-y
ear r
elat
ive
surv
ival
(%)
1984–1986 1987–1989 1990–1992
1993–1995
1996–1998
1999–2001 2002–2004
0 5
10 15 20 25 30 35 40 45 50
Calendar period
<50
50–59
60–69
70–79 80+
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
Outcome of Myeloma Patients
Kumar, Blood 2008
Mieloma Múltiplo
Standard of Care Therapies
FDA Approvals in MM
1960 1970 1980 1990 2000 2010
2006 Thalidomide
2003 Bortezomib
2006 Lenalidomide
2007 Doxil
1983 Autologous Transplantation
1969 Melphalan + Prednisone
1962 Prednisone
1958 Melphalan
Adapted from Kumar SK et al. Blood. 2008;111:2516–2520.
2012 Carfilzomib
2013 Pomalidomide
MM Therapy: Therapeutic Options in the USA
Panobinostat 2014
daratumumab ixazomib
2015
2015 Daratumumab Elotozumab
Ixazomib
Mieloma Múltiplo
Standard of Care Therapies
1960 1970 1980 1990 2000 2010
2006 Thalidomide
2003 Bortezomib
2007 Doxil
1983 Autologous Transplantation
1969 Melphalan + Prednisone
1962 Prednisone
1958 Melphalan
Adapted from Kumar SK et al. Blood. 2008;111:2516–2520.
Carfilzomib
2016
BRASIL
Multiple Myeloma
Transplante / Não-transplante
- Citogenética - ISS - Função Renal - DHL
- Doença Extramedular Standard vs Alto risco
Estratificação
Fatores de risco Idade e PS (< ou > 65/70 anos)
Tratamento individualizado
Multiple Myeloma
Mieloma Múltiplo Recém diagnosticado
Candidato ao transplante autólogo da medula óssea
SIM NÃO
Multiple Myeloma
MPT
MP
VMP
Alkylators-based regimens Alkylators-free regimens
Len-dex
IMiD’s
Six randomized trials: Benefit in PFS… 6m OS... 6m
One randomized trial: Benefit in PFS... 8m OS... 13m
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
One randomized trial: Benefit in PFS & OS vs MPT
Facon T. ASH 2013: abstract number 2
New standards of care of elderly MM pts
Multiple Myeloma
MELFALANO + PREDNISONA +TALIDOMIDA
Multiple Myeloma
MPT vs MP: Meta-analysis of 1685 individual-patient 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
GBRAM Ann Hematol 95:271-278, 2016
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/m2 por 7 dias, prednisona 40mg/m2 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
Multiple Myeloma .
Efficacy endpoint MPT n=32 CTD n=32 P value
(MPT vs CTD)
Response to treatment, %
Complete/very good partial/
partial response
14.3/25.0/28.6 20.7/34.5/34.5
Stable disease/progressive
disease
21.4/10.7 10.3/0
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
• CTD or MPT as suitable frontline regimens for patients with multiple myeloma who are not candidates to transplantation.
Conclusion
Multiple Myeloma
MPT
MP
VMP
Alkylators-based regimens Alkylators-free regimens
Len-dex
IMiD’s
Six randomized trials: Benefit in PFS… 6m OS... 6m
One randomized trial: Benefit in PFS... 8m OS... 13m
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
One randomized trial: Benefit in PFS & OS vs MPT
Facon T. ASH 2013: abstract number 2
New standards of care of elderly MM pts
Multiple Myeloma
MELFALANO + PREDNISONA +BORTEZOMIBE
Mieloma Múltiplo
VMP vs MP in Newly Diagnosed MM (MMY-3002; VISTA)
Patients 65 years of age or older or
not transplant eligible with
untreated MM
(N = 682)
Bortezomib IV 1.3 mg/m2 on Days 1, 4, 8, 11, 22, 25, 29, 32 for four 6-week cycles +
Melphalan and Prednisone*
(n = 344)
Melphalan and Prednisone* for nine 6-wk cycles
(n = 338)
54 weeks
*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.
Bortezomib IV 1.3 mg/m2 on Days 1, 8, 22, 29 for
five 6-week cycles + Melphalan and Prednisone*
(n = 344)
Mieloma Múltiplo
VMP vs MP in Newly Diagnosed MM (MMY-3002; VISTA): Response to Treatment
Resp
onse
to
Trea
tmen
t (%
)
VMP (n = 336) MP (n = 331)
0
20
40
60
80
100
82
50
35
46
ORR (CR + PR)
CR (IF-)
P < .000001
P < .000001
5
45
10
PR VGPR
5
• 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
San Miguel JF, et al. ASH 2007. Abstract 76.
Multiple Myeloma
Bortezomib + MP (VMP) vs MP – 682 patients
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
Multiple Myeloma
MPT
MP
VMP
Alkylators-based regimens Alkylators-free regimens
Len-dex
IMiD’s
Six randomized trials: Benefit in PFS… 6m OS... 6m
One randomized trial: Benefit in PFS... 8m OS... 13m
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
One randomized trial: Benefit in PFS & OS vs MPT
Facon T. ASH 2013: abstract number 2
New standards of care of elderly MM pts
Multiple Myeloma FIRST: Phase 3 trial of Lenalidomide + low-dose Dex vs MPT (IFM 07-01; MM-020)
*In patients aged > 75 years: Dex 20 mg/day, melphalan 0.20 mg/kg/day, thalidomide 100 mg/day
N = 1,623
• Previously untreated MM
• Age ≥ 65 years or not eligible for a transplant
• No neuropathy of grade > 2
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
RANDOMIZATION
Facon et al. ASH 2013: abstract 2
Multiple Myeloma
Continuous Rd reduced the risk of disease progression by 28% vs. MPT
mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, Lenalidomide plus low-dose dexamethasone.
Median PFS Rd (n= 535) 25.5 mos Rd18 (n= 541) 20.7 mos MPT (n= 547) 21.2 mos
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
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
Time (months)
Pat
ient
s (%
)
100
80
60
40
20
0 0 6 12 18 24 30 36 42 48 54 60
72 w
ks
Facon T, et al. Blood. 2013;122:abstract 2.
FIRST trial: PFS
Multiple Myeloma
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
4-year OS Rd (n= 535) 59.4% Rd18 (n= 541) 55.7% MPT (n= 547) 51.4%
Overall survival (months) 0 6 12 18 24 30 36 42 48 54 60
Pat
ient
s (%
)
100
80
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
FIRST trial: OS interim analysis (574 deaths. 34%)
Facon T, et al. Blood. 2013;122:abstract 2.
Multiple Myeloma
TRATAMENTO Equilibrar eficácia vs toxicidade
Multiple Myeloma
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
Age < 75 years Age > 75 years
1.00
0.
75
0.50
0.
25
0.00
Pro
babi
lity
of s
urvi
val (
%)
0 0.5 1 1.5 2 2.0 3
< 75 years > 75 years
3-year OS 68% 57%
Time since diagnosis (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
0.75
0.50
0.25
0.00
0 0.5 1 1.5 2 2.0 3
Pro
babi
lity
of s
urvi
val (
%)
No grade 3 to4 non-hematological Aes Grade 3 to 4 non-hematological AEs
Time since diagnosis (years)
1.00
0.75
0.50
0.25
0.00
0 0.5 1 1.5 2 2.0 3
No discontinuation due to AEs Drug discontinuation due to AEs
Time since diagnosis (years) P
roba
bilit
y of
sur
viva
l (%
)
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
Regione Piemonte, Assessorato Sanità 2006
31%
33%
36% 65-74 years 25-64 years
75-101 years
Full-dose chemotherapy
Autologous transplant
Reduced-dose chemotherapy
INCIDENCE: 2002 8.9/100.000
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
patients
Transplantation-eligible
patients
All 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
0 20 40 60 80 100
0
20
40
60
80
100
Time
Surv
ival p
roba
bility
(%)
Number at risk441 227 129 73 16 0
OS median=43 months 38% at 5 years
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
Outcome of Myeloma Patients
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!!! [email protected]