Xavier Leleu

Are We Integrating Biologic Advances in Multiple

Myeloma Into Clinical Practice?

Minimal Residual Disease: A Measurable and Relevant Endpoint

in Treatment

Service d’Hématologie et Thérapie cellulaire Hôpital de la Milètrie, CHU, Poitiers, France

MRD: A Measurable and Relevant Endpoint in Treatment

➢ Depth of response in Myeloma

Are all CR the same

➢ What is MRD

Techniques: NGF vs NGS

Is it just about prolongation of PFS as a surrogate for OS

➢ Prognostic role of MRD

MRD impacts OS

➢ MRD Rate and relevance in current treatment options and strategies

MRD in NDMM

MRD in RRMM

MRD Including high risk MM

➢ Depth of MRD matters

➢Work to do

➢ Conclusion

Treatment advances have increased the likelihood of achieving CR

ORR

VGPR CR

The prognostic impact to CR comes from MRD

Kapoor et al., JCO, 2010 Paiva et al., Blood, 2008

Multicentric, prospective study of 445 NDMM, post ASCT, 1/3 ≥CR

Not reached vs 81 months

P< 0,001

147/295 NDMM (GEM2000) in CR post ASCT. MRD by MFC at day 100 afterASCT.

5-year OS rates 87% vs 59%

Lahuerta et al., JCO, 2017

609 NDMM, GEM2000/GEM2005/GEM5010, MRD assessment 9 months after enrolment

Not reached vs 59 months

Minimal Residual Disease, MRD

Immunophenotypic CR.CMF (Sensibilité de 10-4 à 10-8 selon le nombre de couleurs (2 à 10 couleurs))

Molecular CR.ASO-PCR (Se 10-5), NGSNegative MRD < 106

sCR

iCR

mCR

CR

Diagnosis 1012

CR 1010

MRD

Paiva et al., Blood, 2015

MRD is about

Prolongs PFS as a surrogate for OS

Tumor dormancy, the ultimate objective for ‘cure’

Overall effect of MRD on OS

Munshi et al. JAMA Oncol 2017;3:28-35.

MRD-negative status was associated with significantly better OS overall (HR, 0.57; 95%CI, 0.46-0.71; P < .001)

Effect of MRD status on OS in CR patients

MRD-negative status was associated with significantly better OS in CR patients (HR, 0.47; 95%CI, 0.33-0.67; P < .001)

Munshi et al. JAMA Oncol 2017;3:28-35.

IFM 2008

After

induction After ASCT

After

consolidation

Completed

Therapy

n (%) n=31 n=31 n=31 n=31

Negative MRD 4/25 (16) 14/26 (54) 15/26 (58) 21/30 (70)

sCR + CR 7 (23) 14 (45) 15 (48) 18 (58)

≥ VGPR 18 (58) 21 (68) 26 (84) 26 (84)

Roussel et al. JCO 2014

Phase 2. 31 NDMM, VRD x 3 - Transplant - VRD x 2 - Rev 1 year

MRD at 10-4-10-5

Response-evaluable set. Assessed by next generation

sequencing (NGS) in bone marrow.

Avet-Loiseau H. Oral presentation at IMW 2017. New Delhi, India.

POLLUX: DRd vs Rd - MRD-negative rate

DRd

Rd

0

10

20

30

40

50

MR

D-n

eg

ati

ve

ra

te (

%)

MRD- (10−4) MRD- (10−5) MRD- (10−6)

30%

8%

p < 0.0001

23%

5%

p < 0.0001

10%

2%

p < 0.0001

Pro

gre

ss

ion

fre

e a

nd

alive

(%

)

0

20

40

60

80

100

0 3 6 9 12 15 21 27

Months

2418

Rd MRD–

DRd MRD–

DRd MRD+

Rd MRD+

Phase 3 multicenter, early RRMM PFS

POLLUX: MRD by Cytogenetic Risk Status (10–5)

Weisel K et al., ASCO 2017

**P = 0.0009. ***P = 0.0001. aPercentage of patients within a given risk group and treatment arm.

21

32

0

12

0

5

10

15

20

25

30

35

High risk Standard risk

MR

D-n

egative p

atients

per

risk g

roup,

%a

** ***

DRd

n = 28

Rd

n = 37

DRd

n = 133

Rd

n = 113

MRD-negative rates PFS in high-risk patients

% s

urv

ivin

g w

ith

ou

t p

rogre

ssio

n0

20

40

60

80

100

0 3 6 9 12 15 18 33

Months

21 24

Rd MRD positive

DRd MRD negative

27

DRd MRD positive

30

In POLLUX, high-risk patients treated with daratumumab achieve MRD negativity and remain progression free

ClinicalTrials.gov Identifiers: NCT02136134

P-value (trend) : p<0.0001

<10-6

[10-6;10-5[[10-5;10-4[

>=10-4

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0P

atients

without

progressio

n (

%)

40 40(0) 40(0) 40(0) 33(6) 23(9) 15(6) 4(4) 2(1)[10-4;10

-3[

23 23(0) 23(0) 23(0) 22(1) 19(3) 14(2) 3(5) 2(0)[10-5;10

-4[

29 29(0) 29(0) 29(0) 28(0) 22(5) 16(3) 4(4) 1(1)[10-6;10

-5[

86 86(0) 86(0) 86(0) 86(0) 77(5) 61(3) 36(5) 10(0)<10-6

N at risk(events)

06

1218

2430

3642

48

Months since randomization

MRD at post-maintenance

Phase 3 multicenter, IFM/DFCI 2009, NDMM

Depth of MRD matters

RVDx3

RVD x 2

RVD x 5

Revlimid 12 mos

Melphalan 200mg/m2* +

ASCT

CY (3g/m2) MOBILIZATIONGoal: 5 x106 cells/kg

RVDx3

CY (3g/m2)MOBILIZATIONGoal: 5 x106 cells/kg

Randomize

Revlimid 12 mos

Avet-Loiseau H. Oral presentation at IMW 2017. New Delhi, India.

IFM 2009 trial

Role of treatment

P<0.001

0

25

50

75

100

Pa

tie

nts

(%

)

40 39 34 31 17 1negative MRD_RVD50 47 43 38 23 4negative MRD_Transp66 51 38 21 11 2positive MRD-RVD68 62 49 35 15 1positive MRD-Transplant

N at risk

0 12 24 36 48 60

Time since MRD assessment

positive MRD-Transplant

positive MRD-RVD

negative MRD_Transp

negative MRD_RVD

IFM 2009 trial

Role cytogenetics

P<0.001

0

25

50

75

100

Pa

tie

nts

(%

)

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

Keats et al., Blood, 2012

Work to do (1), MRD and – Clonal selection

21%

64%

58%

19%

17%

71%

78%

0%0%

95%

Remissio

n ~2N

Diagnosis

~2N

Relapse 1

~2N

Relapse 2

~2N

Relapse 3

~2N

Plasmacytoid

Phenotype

37%

Relapse 4

~3NPlasma cell

leukaemia

~3N

Lymphoid

Phenotype

34%

Lymphoid

phenotype

63%

Clone 1.1

Clone 1.2

Clone 2.1

Clone 2.2

Misc

Lenalidomide/dexamethasone

Plasmacytoid

Phenotype

66%

Melphalan/prednisone/ bortezomib (MPV)

72%

0%

64%

31%

Bortezomib SGN-40

0%0%

96%

Morgan et al., Oral communication

P-value : p=0.0002

Negative (<10-6)

Positive

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pa

tients

without

pro

gre

ssio

n (

%)

84 84(0) 83(1) 78(5) 74(3) 59(13) 41(5) 17(6) 6(2)MRD positive

79 79(0) 79(0) 77(2) 75(2) 68(4) 51(3) 30(2) 8(0)MRD neg (<10-6)

N at risk(events)

06

1218

2430

3642

48

Months since randomization

MRD at pre-maintenance for MRD neg (FCM)

Work to do (2) MRD and – Best timing

P-value : p=0.0006

Negative (<10-6)

PositivePositive

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pa

tients

without

pro

gre

ssio

n (

%)

42 42(0) 42(0) 42(0) 38(3) 31(7) 21(4) 5(5) 1(1)MRD positive

69 69(0) 69(0) 69(0) 69(0) 63(4) 50(2) 29(4) 9(0)MRD neg (<10-6)

N at risk(events)

06

1218

2430

3642

48

Months since randomization

MRD at post-maintenance for MRD neg (FCM)

Avet-Loiseau H. Oral presentation at IMW 2017. New Delhi, India.

Work to do (3) MRD and – MGUS like profile

Paiva et al., Leukemia, 2013

Work to do (4) MRD study

Zamagni et al, Blood 2011 Moreau et al, Oral communication

Various ways to study the BM, BM sampling, PET CT ….

Thal/dex followed by tandem ASCT IFM 2009/DFCI - Imajem

p=0.000424

Months

Switch PET CT -

Switch PET CT +

MRD1 MRD2

Standard Risk

PI+ImidsD-

MoAB

x6

PI+ImidsD-

MoAB

x6

↗

- R

↘

HDT1 +

PI+ImidsD-MoAB

X4

PI+ImidsD-MoAB

x7

→

↗ Maint A

R ↘ Maint B

+

HDT1 +

PI+ImidsD-

MoAB*

x6

*diff PI, Imids,..

+ HDT2

↗ Maint C

→ R ↘ Maint D

- R

↗ Maint A

↘ Maint B

High Risk

PI+ImidsD-

MoAB

x6

→HDT1 +

PI+ImidsD-

MoAB*

x6

*diff PI, Imids,..

→ HDT2 → Maint C or D

IFM 2018

Attal M – IFM - Confidential

Work to do (5) MRD and – treatment decision

Minimal Residual Disease Assessment:

Not Relevant for Clinical Practice Yet

Sagar Lonial, MDChair and Professor

Department of Hematology and Medical OncologyChief Medical Officer, Winship Cancer Institute

Emory University School of Medicine

There are patients with old drugs and

old tests that do well..

Martinez-Lopez et al, Blood 2011

Functional cure?

Impact of MRD: Meta-analysis

Are these the same patients?

Munshi et al, JAMA Oncol. 2017;3(1):28-35.

Getting to Minimal Residual Disease

(MRD): New Definitions for CR

S.S. Patient

1×1012

Stringent CR

NGS CR 1×10-6

?Cure?

Disease burden

Newly diagnosed

0.

0

Antibodies

Genomic

Based Tx

CR

MRD Flow CR 1×10-5

P-value (trend) : p<0.0001

<10-6

[10-6;10-5[

[10-5;10-4[

>=10-4

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pa

tients

without

progressio

n (

%)

79 79(0) 70(9) 59(11) 50(9) 38(11) 28(6) 6(9) 0(3)[10-4;10

-3[

49 49(0) 47(2) 45(2) 43(2) 34(7) 22(4) 8(6) 2(0)[10-5;10

-4[

31 31(0) 30(1) 28(2) 27(0) 22(4) 17(1) 8(2) 4(1)[10-6;10

-5[

87 87(0) 87(0) 85(2) 83(2) 74(6) 54(4) 31(3) 8(0)<10-6

N at risk(events)

06

1218

2430

3642

48

Months since randomization

MRD at pre-maintenance

How you measure MRD impacts the

results

P-value (trend) : p<0.0001

<10-6

[10-6;10-5[[10-5;10-4[

>=10-4

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pa

tients

without

progressio

n (

%)

40 40(0) 40(0) 40(0) 33(6) 23(9) 15(6) 4(4) 2(1)[10-4;10

-3[

23 23(0) 23(0) 23(0) 22(1) 19(3) 14(2) 3(5) 2(0)[10-5;10

-4[

29 29(0) 29(0) 29(0) 28(0) 22(5) 16(3) 4(4) 1(1)[10-6;10

-5[

86 86(0) 86(0) 86(0) 86(0) 77(5) 61(3) 36(5) 10(0)<10-6

N at risk(events)

06

1218

2430

3642

48

Months since randomization

MRD at post-maintenance

Avet-Loiseau et al, ASH 2015

MRD testing is not a surrogate for

Cure

Lahuerta et al, JCO 2017

MRC Myeloma IX: PFS and OS Do Not Plateau

• MRD negativity at Day 100 post-ASCT was

associated with improved PFS (P<0.0001) and OS

(P=0.0183)PFS OS

MRD status at Day 100 post-ASCT: MRD– n=247; MRD+

n=150 1. Rawstron AC, et al. J Clin Oncol)

MRD– 28.6 months

MRD+ 15.5 months

PF

S (

%)

Months since MRD assessment

0 12 24 36 48 60 72

84 96

Median PFS1009080

70

6050

403020

10

0

Numbers at risk:

MRD– 200 145 107 73 41

20 2 0

MRD+ 87 59 42 24 14

7 0 0

Months since MRD assessment

0 12 24 36 48 60 72

84 96

OS

(%

)

1009080

70

6050

403020

10

0

MRD– 80.6 months

MRD+ 59.0 months

Median OS

Numbers at risk:

MRD– 237 220 197 157 92

43 9 0

MRD+ 132 124 105 83 46

25 1 0

P-value (trend) : p<0.0001

<10-6

[10-6;10-5[[10-5;10-4[

>=10-4

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pa

tients

without

pro

gre

ssio

n (

%)

40 40(0) 40(0) 40(0) 33(6) 23(9) 15(6) 4(4) 2(1)[10-4;10

-3[

23 23(0) 23(0) 23(0) 22(1) 19(3) 14(2) 3(5) 2(0)[10-5;10

-4[

29 29(0) 29(0) 29(0) 28(0) 22(5) 16(3) 4(4) 1(1)[10-6;10

-5[

86 86(0) 86(0) 86(0) 86(0) 77(5) 61(3) 36(5) 10(0)<10-6

N at risk(events)

06

1218

2430

3642

48

Months since randomization

MRD at post-maintenance

Cannot use MRD to decide who gets a

transplant

2/3 of these

patients were

from HDT, 1/3

from delayed

HDT

Avet-Loiseau et al, ASH 2015

MRD changes post transplant do not

impact OS

Lahuerta et al, JCO 2017

Conclusion

YES. Minimal Residual Disease is

A Measurable and Relevant Endpoint in Treatment

➢ Is manageable in most countries

➢ Has demonstrated a prognostic role, PFS and OS

➢ You already have implemented depth of response in your practice for

treatment decision

- You decide a treatment strategy based on known depth of response

- You optimize a treatment scheme to improve depth of response, ASCT,

consolidation, maintenance…

➢ Time for the next step, MRD-based treatment choice decision making

Summary (Fallacies) of MRD testing

➢ MRD is a surrogate for cure

➢ If you are MRD negative, you can stop

treatment

➢ If you are MRD positive after transplant, you

need to change from standard treatment

➢ MRD is the only predictor of good long term

outcomes

➢ If you convert from MRD negative to MRD

positive, you need to change therapy

➢ MRD assessment in the marrow is enough to

declare victory

What can MRD testing be used for

➢ Comparing across clinical trials

➢ Assessing efficacy of new treatment

approaches

➢ Prognosis

But not for current clinical decision making

There are too many unknowns that will be

addressed by ongoing trials

Thank you for your attention

Never give up!