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

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



Overall survival



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


Len-dex

IMiD’s







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


Len-dex

IMiD’s







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]

mieloma múltiplo tratamento do idoso -...

Documents