MRD Driven Therapy“Pro”

Jesús San Miguel

Universidad de NavarraSpain

Minimal residual disease (MRD) undetectable by conventional methods that define response criteria

107

106

105

104

103

102

101

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

108

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)