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MRD Driven Therapy“Pro”
Jesús San Miguel
Universidad de NavarraSpain
Minimal residual disease (MRD) undetectable by conventional methods that define response criteria
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10
0
Presentation
PR
VGPR
CR
stringent CR
Tota
l num
ber o
f tum
or c
ells
MRD
Undetectable MRD
(Operational cure)
Time to progression
-
-
-
-
-
-
-
-
-
-Diagnosis End of
therapy
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Paiva B, Van Dongen JJ, Orfao A. Blood. 2015;125(20):3059-3068
MRD by ‐ Flow (NGF)‐ Sequencing (NGS)‐ Imaging (PET)
Zamagni E. et al, Blood 2011;118(23):5989Zamagni E, et al. Clin Cancer Res 2015;21(19):4384-90
ASCT candidates (192 pts)
3m post-ASCT: Complete FDG suppression at PET/CT ……Longer PFS & OS
p = 0.003
94.6%
69.9%
p < 0.001
69%
51.6%
PFS
OS
IFM 2009: PET‐CT normalisation before maintenanceImpact on PFS and OS (62% normalised)
Moreau P, et al. Blood 2015 126:395
Predictive value of PET/CT after treatment in MM patients: The concept of PET CR
MRD met the key requirements for a surrogate endpoint for survival and treatment monitoring
• move the PFS of patients in remission from 3-5y to 8-10y
Surpesede CR
confirmed by different techniques & Labs
Predicts outcome upon different MRD rates
Predicts in Newly Diagnosed ( Trx & non-Trx) and Relapsed patients
Impact on High and Standard Risk Patients ( overcome high risk)
Highly Reliable
Critical analysis on the value of MRD versus CR Patients attaining CR experience prolonged PFS and OS…but…
GEM2000, GEM2005MENOS65, GEM2005MAS65, GEM2010MAS65
Pro
gres
sion
-free
sur
viva
l (%
)
Time from diagnosis (months)
CR (n=548) median PFS: 56 monthsnCR (n=249) median PFS: 43 monthsPR (n=535) median PFS: 33 months<PR (157) median PFS: 20 months
P <.001
CR vs nCR: P <.001nCR vs PR: P =.004PR vs <PR: P <.001
Ove
rall
surv
ival
(%)
Time from diagnosis (months)
CR (n=548) median OS: 108 monthsnCR (n=249) median OS: 91 monthsPR (n=535) median OS: 73 months<PR (157) median OS: 35 months
P <.001
CR vs nCR: P =.09nCR vs PR: P <.001PR vs <PR: P <.001
100
80
60
40
20
0
0 50 100 150 200
100
80
60
40
20
0
0 50 100 150 200
PFS OS
Lahuerta JJ, Paiva B, et al. J Clin Oncol 2017; doi: 10.1200/JCO.2016.69.2517
GEM trials: CR (n=1.230)and MRD (n=797)
Pro
gres
sion
-free
sur
viva
l (%
)
Time from MRD assessment (9 months after study enrollment)
MRD-, median PFS: 63 monthsCR, median PFS: 27 monthsnCR, median PFS: 27 monthsPR, median PFS: 29 months<PR, median PFS: 11 months
MRD- vs CR: P <.001CR vs nCR: P =.616nCR vs PR: P =.962PR vs <PR: P <.001
Ove
rall
surv
ival
(%)
MRD-, median OS: Not reachedCR, median OS: 59 monthsnCR, median OS: 64 monthsPR, median OS: 65 months<PR, median OS: 28 months
MRD- vs CR: P <.001CR vs nCR: P =.594nCR vs PR: P =.912PR vs <PR: P =.024
P <.001 P <.001
Time from MRD assessment (9 months after study enrollment)
The true value of CR relies in the MRD status, and CR w/o MRD is no better than PR
Lahuerta JJ, Paiva B, et al. J Clin Oncol 2017; doi: 10.1200/JCO.2016.69.2517.
GEM trials: CR (n=1.230)and MRD (n=797)
Impact of MRD across MM patient’ subgroups
-0.3 0.2 0.7 1.2
Overall
Transplant eligible
Transplant ineligible
ISS I
ISS II
ISS III
Standard-risk FISH
High-risk FISH
Reduced risk after MRD-
-0.3 0.2 0.7 1.2
Overall
Transplant eligibleTransplantineligible
ISS I
ISS II
ISS III
Standard-risk FISH
High-risk FISH
Reduced risk after MRD-
Progression-free survival Overall survival
Lahuerta JJ, Paiva B, et al. J Clin Oncol 2017; doi: 10.1200/JCO.2016.69.2517.
MRD negativity is associatted with 60% and 70% reductionin risk of relapse and death respectively.
MRD met the key requirements for a surrogate endpoint for survival and treatment monitoring
• move the PFS of patients in remission from 3-5y to 8-10y
Surpesede CR
confirmed by different tecniques & Labs
Predicts outcome upon different MRD rates
Predicts in Newly Diagnosed ( Trx & non-Trx) and Relapsed patients
Impact on High and Standard Risk Patiens ( overcome high risk)
Highly Reliable
MRD in transplant-eligible MM
0 224 177 86 4458 187 136 50 4
Time from diagnosis (months)Number at riskMRD-positiveMRD-negative
MRD+ MRD-
Median PFS, months 40 NR
HR (95% CI) 0.1 (0.06 – 0.2); P <.001
Pro
gres
sion
-free
sur
viva
l (%
)
0
25
75
100
50
0 10 20 30 40
MRD assessment by NGF in GEM2012MENOS65
Paiva B, et al. Blood 2017;130: abstract 905
MRD assessment by NGS in IFM/DFCI 2009
Avet-Loiseau H, et al. Blood 2017;130: abstract 435
P<0.001
B
0
25
50
75
100
Patients
(%
)
87 83 74 39 8negative MRD146 94 54 22 1positive MRD
N at risk
0 12 24 36 48
Time since MRD assessment
positive MRD
negative MRD
< 10‐6
> 10‐6
Oliva S, et al. J Clin Oncol 35, 2017 (suppl; abstr 8011)
MRD assessment by FC in EMN02/H095
MRD by FC Prognostic Significance UK XI
De
0 49 36 10 10 54 43 20 1
458 84 57 20 2
0 224 177 86 4
0
25
75
100
50
0 10 20 30 40
Number at riskMRD-negMRD ≥2x10-6 to <10-5
MRD ≥10-5 to <10-4
MRD ≥10-4
MRD+ ≥10-4 MRD+ ≥10-5 to <10-4
MRD+ ≥2x10-6 to <10-5 MRD-
Median PFS, months 26 NR 40 NR
HR (95% CI) 0.4 (0.3 – 0.5); P <.001
Time from diagnosis (months)
Pro
gres
sion
-free
sur
viva
l (%
)MRD assessment by NGF in GEM2012MENOS65:
impact of persistent MRD before maintenance
Paiva B, et al. Blood 2017;130: abstract 905
MRD assessment by NGS in IFM/DFCI 2009:impact of persistent MRD after maintenance
Avet-Loiseau H, et al. Blood 2017;130: abstract 435
P<0.001
B
0
25
50
75
100
Patien
ts (
%)
32 19 7 2 1=10-423 17 10 4 0[10-5;10-4[29 23 17 10 0[10-6;10-5[87 83 73 39 8<10-6
N at risk
0 12 24 36 48
Time since MRD assessment
<10-6
[10-6;10-5[
[10-5;10-4[
=10-4
MRD in Non-transplant eligible MM
independence from treatment
GEM2000, GEM2005MENOS65, GEM2005MAS65, GEM2010MAS65
Pro
gres
sion
-free
sur
viva
l (%
)
Time from diagnosis (months)
MRD- after ASCT (n=219) median PFS: 72 monthsMRD- after chemotherapy (n=99) median PFS: 59 monthsMRD+ after ASCT (n=263) median PFS: 37 monthsMRD+ after chemotherapy (n=216) median PFS: 30 months
P <.001
100
80
60
40
20
0
0 50 100 150 200
Transplant Non‐TransplantMRD‐MRD+
MRD assessment by NGS in ALCYONE:impact of persistent MRD after induction in elderly MM
Mateos MV, et al. N Engl J Med 2017
6
22
0
5
10
15
20
25
VMP (n = 356) D-VMP (n = 350)
MR
D-n
egat
ive
rate
, %
P <0.0001
3.6X
>3-fold higher MRD-negativity rate with D-VMP; Lower risk of progression or death in all MRD-negative patients
% s
urvi
ving
with
out p
rogr
essi
on
0
20
40
60
80
100
0 3 6 9 12 15 18 27Months
2278334272
2278281244
2278254234
2277239221
2175210210
1458113121
8315362
0000
0228
No. at riskVMP MRD negative
D-VMP MRD negativeVMP MRD positive
D-VMP MRD positive
21 24
4141421
VMP MRD negative
VMP MRD positive
D-VMP MRD negative
D-VMP MRD positive
MRD in relapsed/refractory
Chemotherapy and/or ASCT
HR: 2.8; 95% CI:1.0–7.6 P=0.039
Tim
e to
pro
gres
sion
(%)
MRD-positive
100
80
60
40
20
0
Time from MRD assessment (months)
Median: 75 months
Median: 14 months
MRD monitoring among R/R patients reaching CR after salvage therapy
Paiva B, et al. Haematologica. 2015;100:e53–5
0 20 40 60 80 100 120 140 160 180
MRD-negative
Dimopoulos MA, et al. Blood 2017;130: abstract
MRD assessment by NGS in Pollux and Castor: impact of achieving MRD-negativity (10-5)
Pollux Castor
Spencer S, et al. Blood 2017;130: abstract 3145
Impact on High and Standard Risk patients
90 40 27 12 0300 126 93 31 30 33 28 14 20 151 122 59 1
0
25
50
75
100
0 10 20 30 40
HR & MRD+
SR & MRD+
HR & MRD-
SR & MRD-
Median PFS, months 27 35 NR NR
One-sided P- .025 0.56
Time from diagnosis (months)
Pro
gres
sion
-free
sur
viva
l (%
)
Number at riskSR FISH & MRD-negHR FISH & MRD-negSR FISH & MRD-posHR FISH & MRD-pos
HR FISH: t(4;14), t(14;16) and/or del(17p)
MRD assessment by NGF in GEM2012MENOS65: impact of cytogenetic risk?
Paiva B, et al. Blood 2017;130: abstract 905
MRD assessment by NGS in IFM/DFCI 2009: impact of cytogenetic risk?
Avet-Loiseau H, et al. Blood 2017;130: abstract 435
P<0.001
0
25
50
75
100P
atients
(%
)
56 54 48 43 25 4neg.MRD-Stdard Risk18 17 14 12 5 1neg.MRD-High Risk82 73 59 42 21 3pos.MRD-Stdard Risk28 19 11 5 4 0pos.MRD-High Risk
N at risk
0 12 24 36 48 60
Time since MRD assessment
pos.MRD-High Risk
pos.MRD-Stdard Risk
neg.MRD-High Risk
neg.MRD-Stdard Risk
Outcome of high-risk elderly patients attaining MRD-negativity (8-color flow)
Standard-risk FISH / MRD– (n=40); median TTP: NR
High-risk FISH / MRD– (n=7); median TTP: NR
Standard-risk FISH / MRD+ (n=66); median TTP: 15 mos
High-risk FISH / MRD+ (n=19); median TTP: 12 mos
50403020100
100
80
60
40
20
0
Tim
e to
Pro
gres
sion
(%)
P <.001
Time From MRD Assessment (Mos)
P =.70
P =.02
Paiva B, et al. Blood. 2016;127:3165-3174.
MRD at 10–5 by Cytogenetic Risk by NGS
No high-risk MRD negative patients have progressed or converted to MRD positive– High risk = any of t(4;14), t(14;16), del17p– Standard risk = conclusive absence of all 3 markers
26
CASTORPOLLUX
1412
02
0
5
10
15
20
25
30
35
High risk Standard risk
MR
D-n
egat
ive
patie
nts
per r
isk
grou
p, %
a
18
30
0
10
0
5
10
15
20
25
30
35
High risk Standard risk
MR
D-n
egat
ive
patie
nts
per r
isk
grou
p, %
a
P values calculated using likelihood-ratio chi-square test.aPercentage of patients within a given risk group and treatment arm.bPercentage of patients within a given treatment arm within the biomarker-evaluable population.
**
*** P <0.0001** P <0.005
*** ** **
n = 28 n = 37 n = 133 n = 113 n = 123 n = 135n = 44 n = 51
DRd (17% high riskb) Rd (25% high riskb) DVd (26% high riskb) Vd (27% high riskb)
In high-risk patients, MRD-negative status was achieved only in those treated with daratumumab-containing regimens
Drara + Rd (Pollux ) or Vd (Castor) : MRD in Patients of High Cytogenetic Risk Status (10–5)
aPercentage of patients within a given risk group and treatment arm.
Pollux
27
Castor
No. at risk
% s
urvi
ving
with
out p
rogr
essi
on
0
20
40
60
80
100
0 3 6 9 12 15 18 33Months
21 24
Rd MRD positive
DRd MRD negative
Rd MRD negativeDRd MRD negative
Rd MRD positiveDRd MRD positive
27
063722
063216
062115
061813
061513
061512
061310
0000
06108
06107
0440
DRd MRD positive
0200
30No. at risk
% s
urvi
ving
with
out p
rogr
essi
on
0
20
40
60
80
100
0 3 6 9 12 15 18 27
Months21 24
Vd MRD positive
DVd MRD negative
Vd MRD negativeDVd MRD negative
Vd MRD positiveDVd MRD positive
065138
063232
062328
061320
06415
06214
0318
0000
0002
0001
DVd MRD positive
MRD met the key requirements for a surrogate endpoint for survival and treatment monitoring
• move the PFS of patients in remission from 3-5y to 8-10y
Surpesede CR
confirmed by different tecniques & Labs
Predicts outcome upon different MRD rates
Predicts in Newly Diagnosed ( Trx & non-Trx) and Relapsed patients
Impact on High and Standard Risk Patiens ( overcome high risk)
Highly Reliable
MRD to predict relapse
MRD reappearance during follow-up monitoring predicts clinical relapses
MRD reappearance
Patients in CR + Flow CRafter up-front treatment
MRD monitoring during f/up
MRD reappearance:85% had clinical
relapse
Paiva B, et al. EHA 2014. abstract S698 (oral presentation) Ferrero S, et al. Leukemia. 2015;29(3):689-95
If MRD is the most relevant prognostic factor why we do
not use MRD to drive therapy?
If MRD is the most relevant prognostic factor why we do
not use MRD to drive therapy?
UK group: RADAR study. Risk adapted therapy according to response. NDMM transplant eligible
UK group: RADAR study. Risk adapted therapy according to response. NDMM transplant eligible
IFM 2019 IFM 2019
MRD monitoring
GEM2014MAIN: role of MRD in optimizing duration of maintenance
Rd
Ixazomib-RdRdMRD+
MRD- No maintenance
R S
MRD monitoring
MRD monitoring
2-years 3-years
MRD monitoring
MRD monitoring
NCT02406144
36
aDuring the first cycle (6 weeks), bortezomib is given on D1, 4, 8, 11, 22, 25, 29, and 32.; GAH: J Geriatr Oncol. 2015 Sep;6(5):353-61; R1: first randomization; R2: second randomization ; IMF imnunofenotipic response NGF ( next generation flow)
NDMM patientsNS CTC
>65 yn= 462 elderly
Fit Patients(GHA)
ARM 2a KRd .N=154
ARM 1 VMP+Rd
(R1) Induction 18 cycles (R2) MaintenanceConsolidation
RdDar
Four cycles Dara+R
No maintenance
MRD9 cy
MRD18 cy
MRD22 cy
Dara+R
ARM 2b KRD- DARA n=154
No maintenance
Primary endpoint immonuphenotipic complete response Secondary exploratory outcome: PFSPrimary endpoint immonuphenotipic complete response Secondary exploratory outcome: PFS
MRD+
MRD-
Directly to the R2 maintenance fase
*
*
* Patientes in Biological relapse will be rechallenge by Dra + R
Design GEMFIT2016
The Treatment Goal for Cancer (including MM)
Cure…..or at least… Prolong Survival & QoL
The Treatment Goal for Cancer (including MM)
Cure…..or at least… Prolong Survival & QoL
Relevant biomarkers for survival & treatment decission
‒ Frailty
‒ Genetics
‒ Response & duration
“The dream of cure ……….to erradicate all tumor cells”
sensitive methods to measure tumor depletion
Relevant biomarkers for survival & treatment decission
‒ Frailty
‒ Genetics
‒ Response & duration
“The dream of cure ……….to erradicate all tumor cells”
sensitive methods to measure tumor depletion
HospitalesClínico de Barcelona12 Octubre (Madrid)
Clínico de SalamancaClínico de San Carlos (Madrid)
Hospital de BadalonaClínico de AsturiasFr. Peset (Valencia)
Universitario de CanariasRio Ortega (Valladolid)
Cínico de ZaragozaHospital General de Jerez
Ramón y Cajal (Madrid)Morales Meseguer (Murcia)
La Fe (Valencia)C.U. de Navarra
Galdakao (Vizcaya)Clínico de ValladolidSant Pau (Barcelona)
Arnau Vilanova (Lérida)Universitario de Santiago
General Universitario de ValenciaUniversitario de Getafe (Madrid)
Insular de las PalmasH. de La Princesa (Madrid)
Severo Ochoa (Madrid)Juan XIII (Tarragona)
ToledoGandía (Valencia)
Vall D´Hebrón (Barcelona)San Jorge (Huesca)
Verge de la Cinta (Tortosa)Alarcos (Ciudad Real)
Mataró (Madrid)Juán Canalejo (Coruña)
Ferrol
HospitalesGeneral de Segovia
Cruces (Bilbao)St. Coloma de Gramanet
(Barcelona)Gregorio Marañon (Madrid)
Carlos Haya (Málaga)H. Tauli (Gerona)
HuescaPalencia
Alcira (Valencia)H. Del Mar (Barcelona)
Mahón (Baleares)Clínico de MálagaXeral Cies (Vigo)
PlasenciaCáceres
AlgecirasÁvilaJaén
S. Pau i Sta Tecla (Tarragona)General de Guadalajara
Sagunto (Valencia)Son Dureta (Mallorca)
CuencaAlicante SUS
M. Valdecilla (Santander)Albacete
H. Del BierzoFundación Jiménez Díaz
(Madrid)Elda (Alicante)
V. Del Rosel (Cartagena)Castellón
Mutua TarrasaConsorcio Tarrasa
C. Corachán (Barcelona)
Salamanca: A. Orfao; Mv Mateos; N. Puig, E Ocio; N. Gutierrez; R Garcia-Sanz, Flores-Montero J
Navarra: B. Paiva, P Maiso, P. Rodriguez, MJ Calasanz, F Prosper
J Blade JJ Lahuerta
Grupo Español de Mieloma (GEM)