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

ara

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