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Mieloma Múltiplo: Na Era de Novos Agentes e Terapias Continuadas na Recidiva, ainda há papel para o 2º Transplante Autólogo ?
Prof. Angelo Maiolino, M.D. , PhD
Professor of Medicine, Universidade Federal do Rio de Janeiro
Coordinator, Hematology Service, Americas Centro de Oncologia Integrado Rio de Janeiro
Member of the International Myeloma Working Group
C0- Chair, GBRAM – Grupo Brasileiro de Mieloma Múltiplo
Disclosure:
• Consultancy: Janssen, Takeda, Amgen, Celgene, Bristol,Sanofi,Abbvie
• Research Funding: not applicable
• Honoraria: Janssen, Takeda, Amgen, Celgene, Sanofi,Bristol
• Patents and Royalties: not applicable
• Membership on an Entity’s Board of Directors or Advisory Committees: Board of Directors
Associação Brasileira de Hematologia e Hemoterapia
• Member of International Myeloma Working Group
• Discussion of off-label drug use: not applicable
Da
te o
f p
rep
ara
tion: M
arc
h 2
01
7 M
M1
60
07
2u
Continuing evolution of multiple myeloma treatment:
selected new classes and targets 2016–2017
IMiD, immunomodulatory drug; HDAC, histone deacetylase
*Not yet FDA-approved for MM; available in clinical trials Adapted from Richardson PG. et al ASH 2015, MMRF 2016
1st Generation novel agents 2nd Generation novel therapies/Immunotherapy
Targeted Therapy
Monoclonal antibodyProteasome inhibitor IMiD HDAC inhibitor
Adoptive T cell therapy VaccinesCheckpoint inhibitors
20122003 2006 2007 2013 2015 2017+
Ixazomib
Bortezomib + Doxil
Carfilzomib
Bortezomib
Thalidomide
Lenalidomide
Pomalidomide
Panobinostat
Elotuzumab
Isatuximab*
CAR-T*
Atezolizumab*Durvalumab*
Nivolumab*Pembrolizumab*
Vaccines*
Daratumumab
AC-241/1215*
3rd Generation IMiDs*
Melflufen*Selinexor*
Venetoclax*Nelfinavir*
Marizomib*
Oprozomib*
History of Multiple Myeloma Treatment US Regulatory Approvals1,2
RRMM
NDMMNot MM-specifica
aDate indicates first approval of agents commonly used for the treatment of MM, although MM was not indicated on the historical label.
Dex, dexamethasone; NDMM, newly diagnosed multiple myeloma; RRMM, relapsed/refractory multiple myeloma.
1. Kyle RA and Rajkumar SV. Blood. 2008;111:2962-2972. 2. http://www.fda.gov.
1960 1970 1980 1990 2000 2010 2020
Melphalan
Vincristine Carmustine
Doxorubicin
Thalidomide
+ dex
Lenalidomide
+ dex
Pomalidomide
+ dex
Carfilzomib +
lenalidomide
+ dex
Carfilzomib
+ dex
Lenalidomide
+ dex
Carfilzomib
Bortezomib
Bortezomib
Daratumumab +
lenalidomide
+ dex
Daratumumab
+ bortezomib
+ dex
Ixazomib +
lenalidomide
+ dex
Elotuzumab +
lenalidomide
+ dex
Daratumumab
Panobinostat +
bortezomib
+ dex
Post-ASCT
Maintenance
Lenalidomide
USA X Brazil
Mieloma Múltiplo: Na Era de Novos Agentes e Terapias Continuadas na Recidiva, ainda há papel para o 2º Transplante Autólogo ?
Não !
What Does Biology Teach Us? Clonal Tides
clg, cytoplasmic immunoglobulin; MM, multiple myeloma.
Keats JJ, et al. Blood. 2012;120:1067-1076.
Example of clonal dynamics in a patient with MM
58%
19%
Relapse 2
~2N
Clone 1.1Clone 1.2Clone 2.1Clone 2.2Misc.
72%
11%
10%
Diagnosis
~2N
Regimen 1
64%
31%
21%
9%
Remission
~2N
Relapse 1
~2N
Regimen 2Regimen 1 Regimen 3 17%
71%
Relapse 3
~2N
Regimen 4
78%
96%
Relapse 4
~3N
cIg-high
37%
cIg-low
63%
Plasma cell leukemia
~3N
cIg-low
34%
96%
95%
cIg-high
66%
64%
5 unique clones at diagnosis
Variable chemotherapy
response
Minor drug-resistant clone
may become lethal
Mieloma Múltiplo: Na Era de Novos Agentes e Terapias Continuadas na Recidiva, ainda há papel para o 2º Transplante Autólogo
Talvez !?
Relapse after 1st Autologous
Stem-Cell Transplant
Relapse > 18 mt
PAD 2 a 4 cycles
Relapse > 18 months
400 mg/m2 W x 12 W
Baseline
characteristics
Best response after induction and after treatment
Time to progression and Progression free survival
Overall Survival
Da
te o
f p
rep
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tion: M
arc
h 2
01
7 M
M1
60
07
2u
Recent phase 3 data support triplet regimens:
Efficacy
Clinical trial Treatment arms~Median PFS,
monthsHR and p-value ORR, %
PANORAMA-11Bortezomib + dexamethasone and panobinostat
vs placebo12 vs 8
HR 0.63
p<0.0001 61 vs 55
ASPIRE2 Lenalidomide + dexamethasone ± carfilzomib 26 vs 18HR 0.69
p=0.000187 vs 67
ELOQUENT-23 Lenalidomide + dexamethasone ± elotuzumab 19 vs 15HR 0.70
p<0.00179 vs 66
TOURMALINE-MM14Lenalidomide + dexamethasone and ixazomib
vs placebo21 vs 15
HR 0.74
p=0.0178 vs 72
CASTOR5 Bortezomib + dexamethasone ± daratumumab NR vs 7HR 0.39
p<0.000183 vs 63
POLLUX6 Lenalidomide + dexamethasone ± daratumumab NR vs 18HR 0.37
p<0.000193 vs 76
HR, hazard ratio; NR, not reached; ORR, overall response rate; PFS, progression-
free survival; RRMM, relapsed/refractory multiple myeloma
1. San-Miguel JF, et al. Lancet Oncol 2014;15:1195–206. 2. Stewart AK, et al. N Engl J Med
2015;372:142–52. 3. Lonial S, et al. N Engl J Med 2015;373:621–31. 4. Moreau P, et al.
N Engl J Med 2016;374:1621–34. 5. Palumbo A, et al. N Engl J Med 2016;375:754–66.
6. Dimopoulos MA, et al. N Engl J Med 2016;375:1319–31.
Cross-trial comparisons should be interpreted with caution
Daratumumab + lenalidomide and dexamethasone vs lenalidomide
and dexamethasone in RRMM: POLLUX 3-year follow-up
Bahlis et al., ASH 2018; abstract 1996
Updated PFSa
Median follow-up: 44.3 months
D-Rd significantly prolonged PFS vs Rd in
the ITT population (median: 44.5 months vs
17.5 months; HR, 0.44; 95% CI,
0.35-0.55; P<0.0001)
56% reduction in the risk of progression or
death in patients receiving D-Rd
aThe upper bound 95% CI is currently not estimable; median PFS may change with additional follow-up once the upper bound 95% CI estimate is
reached.
PFS in Patients With 1 Prior Line of Therapy
Bahlis et al., ASH 2018; abstract 1996
D-Rd significantly prolonged PFS vs Rd among
patients with 1 prior line of therapy
PFS, progression-free survival; D-Rd, daratumumab/lenalidomide/dexamethasone; CI, confidence interval; Rd, lenalidomide/dexamethasone; HR, hazard ratio.bKaplan-Meier estimate.
Updated PFS By Cytogenetic Risk Status
(NGS and FISH / karyotyping Combined)
Bahlis et al., ASH 2018; abstract 1996
D-Rd prolonged PFS vs Rd
among patients of high-risk or
standard-risk cytogenetic
status
PFS, progression-free survival; D-Rd, daratumumab/lenalidomide/dexamethasone; CI, confidence interval; Rd, lenalidomide/dexamethasone;
HR, hazard ratio; std, standard.
Mundo real Duração do Tratamento e intervalo livre de tratamento por
Linha de terapia- Pacientes Mieloma
Dados de 4997 pacientes(Bélgica, França, Alemanha Italia, Espanha, Suíça e UK)
Yong et al. British Journal of Haematology, 2016, 175, 252–264
Mieloma Múltiplo: Na Era de Novos Agentes e Terapias Continuadas na Recidiva, ainda há papel para o 2º Transplante Autólogo ?
Pacientes com idade inferior a 65 anos no momento da recidiva
Recidiva clinica ou bioquimica de significancia
Duração de resposta após o primeiro Transplante Autólogo superior a 36 meses
Obrigado
angelomaiolino@gmail.com
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