Bruno Paiva University of Navarra, Spain - Comtecmed · Bruno Paiva University of Navarra, Spain 1st World Congress on Controversies in Multiple Myeloma. Bangkok, Thailand. May 11-13

Minimal residual disease

Bruno Paiva

University of Navarra, Spain

1st World Congress on Controversies in Multiple Myeloma. Bangkok, Thailand. May 11-13 2014

1962 1984 1983 1986 1999 1996 2003 2012 2005 2013

Oral melphalan

and prednisone

High-dose

melphalan

High-dose

dexamethasone

VAD (vincristine,

doxorubicin,

dexamethasone)

Autologous bone marrow

transplantation

Bisphosphonates

High-dose therapy with

autologous stem cell

support Proteasome

inhibitors

Bortezomib

Carfilzomib

Ixazomib (MLN 9708)

Phase II/III

Oprozomib (ONX 0912)

Phase I/II

Immunomodulatory drugs

Lenalidomide Thalidomide

Pomalidomide

Adapted from Anderson KC, Bench to bedside translation of targeted therapies in multiple myeloma. ASCO 2011.

Monoclonal

Antibodies

Elotuzumab

Phase II/III

Daratumumab

Phase I/II

MRD

What should be the treatment goal in

MM patients?

To search for an appropriate balance between treatment efficacy, toxicity

& costs

• In very elderly patients (> 80-85y)…….to ensure QoL & avoid additional

costs of expensive treatments

• In fit elderly patients (65-80y) & young ones with severe co-morbidities

……… treatment goal should be to prolong survival and ensure QoL

• In young patients (<65y) …In reference centers & large cooperative

groups……to investigate therapeutic schemes with a cure in the horizon

The paradigm of multiple myeloma

Therapy

M-P

rote

in, g

/dL

2

5

10

ASYMPTOMATIC SYMPTOMATIC

MGUS or

SMOLDERING

MYELOMA

ACTIVE

MYELOMA

1st RELAPSE

PLATEAU

REMISSION

REFRACTORY

RELAPSE

Time

2nd RELAPSE

1. Durie BG. International Myeloma Foundation; 2008:1-40

sustained

disease control

Adapted from Durie BG 1

sustained

disease control

Prolongation of patients survival ultimately requires significant tumor depletion to sustaining/control

minimal residual levels of disease for long periods of time

IMWG uniform response criteria

Stringent CR CR as defined below,

Normal FLC ratio and

Absence of clonal PCs by immunohistochemistry

CR Negative IFE of serum and urine

Disappearance of any soft tissue plasmacytomas, and

< 5% PCs in bone marrow

VGPR Serum and urine M-component detectable by IFE but not on PEP

≥ 90% reduction in serum M-component plus urine <100 mg/24 h

PR ≥ 50% reduction of serum M-protein and reduction in 24-hour urinary

M-protein by ≥ 90% or to < 200 mg/24 hours

If present at baseline, <50% reduction in the size of soft tissue

plasmacytomas is also required Other criteria for non-measurable disease

SD Not meeting criteria for CR, VGPR, PR, or PD

PD Increase of 25% from lowest response value of serum and urine M-

component

Rajkumar SV, et al. Blood. 2011;117(18):4691-4695

San Miguel JF et al. J Clin Oncol. 2013;31(4):448-55

Harousseau JL, et al. Blood. 2010;116(19):3743-3750

Elderly patients (VISTA trial)

RR (CR) (%): 71 (30) vs. 35 (4)

TTP

0 2 4 6 8 10 12 14 16 18 20 22 24 26

100

80

60

40

20

0

Pa

tie

nts

with

ou

t e

ve

nt (%

)

Time (months)

CR

PR

<PR

P<0,004

TTP

0 3 6 9 12

Time (months)

15 18 21 24 27

0

20

40

60

80

100

VMP

MP

Pa

tie

nts

with

ou

t e

ve

nt

(%)

VMP: 24.0 months

MP: 16.6 months, P<0.000001

Transplant-eligible patients (GIMEMA 26866138-

MMY-3006 trial)

Cavo M, et al. Lancet. 2010 Dec 18;376(9758):2075-85

Cavo M, et al. Blood. 2012;120(1):9-19

CR (%) VTD TD P-value

After induction therapy 23% 6% <.0001

After first ASCT 44% 30% .014

After second ASCT 49% 40% .131

After consolidation therapy 61% 47% .012

• Progression-free survival was significantly longer for patients receiving VTD

than in those on TD (HR 0.63, p=0.0061)

1. Lokhorst HM, et al. Haematologica. 2008;93:124-7. 2. Rajkumar SV, et al 2008 J Clin Oncol 26:2171-77. 3. Harousseau JL, et al 2010 J Clin Oncol 28:4621-4629. 4. Rajkumar SV, et al Lancet Oncol 2010; 11: 29–37. 5.

Sonneveld P, et al J Clin Oncol 2012; 30:2946-55. 6. Cavo M, et al Lancet 2010; 376: 2075–85. 7. Reeder CB, et al. Blood. 2010; 115:3416-7. 8. Richardson et al. Blood 2010;116:679-686. 9. Jakubowiak AJ, et al Blood.

2012 30;120:1801-9. 10. Palumbo A, et al. Blood. 2012;120:[abstract 730]. 11. Kumar S, et al . Blood. 2012;120:[abstract 332]. 12. Kumar S, et al. Blood 2012 119: 4375-82.

Pati

en

ts r

esp

on

din

g (

%)

Induction regimen

Selected induction regimens and response in MM

Adapted, Stewart et al Blood 2009

Courtesy of Dr. P. McCarthy. ASH Educational 2013

Prognostic value of depth of response in myeloma

• CR does not mean cure and therefore treatment is not individualized to achieve CR

• Some patients that do not achieve CR have excellent outcome

Several trials in the transplant setting 1-10, non-transplant setting,11-17 after salvage

therapie18-22, or associated to specific stages of treatment (ie. consolidation 23) show a

correlation between depth of response and progression-free survival

Lonial S & Anderson KC. Leukemia. 2013 Jul 19. doi: 10.1038/leu.2013.220

1. Lahuerta JJ, et al. J Clin Oncol 2008; 26: 5775–5782.

2. Moreau P, et al. Blood 2011; 117: 3041–3044.

3. Harousseau JL, et al. J Clin Oncol 2009;27: 5720–5726.

4. Galli M, et al. 2005; 90: 1643–1649.

5. Barlogie B, et al. Cancer 2008; 113: 355–359.

6. Dytfeld D, et al. Leuk Lymphoma 2011; 52: 1271–1280.

7. Gertz MA, et al. Blood 2010; 115: 2348–2353.

8. Kapoor P, et al. J Clin Oncol 2011; 29: (abstract 8069).

9. Alegre A, et al. Bone Marrow Transplant 1998; 21: 133–140.

10. Morgan GJ, et al. Blood. 2011 Aug 4;118(5):1231-8.

11. Oivanen TM, et al. Eur J Haematol 1999; 62: 109–116.

12. Gay F, et al. Blood 2011; 117: 3025–3031.

13. Kyle RA, et al. Cancer 2006; 106: 1958–1966.

14. Offidani M, et al. Blood 2006; 108: 2159–2164.

15. Harousseau JL, et al. Blood 2010; 116: 3743–3750.

16. Palumbo A, et al. J Clin Oncol 2007; 25: 4459–4465.

17. Mateos MV et al. Lancet Oncol 2010 Oct;11(10):934-41

18. Harousseau JL, et al. Haematologica 2010; 95: 1738–1744.

19. Niesvizky R, et al. Br J Haematol 2008; 143: 46–53.

20. Palumbo A, Ann Oncol 2008; 19: 1160–1165.

21. Pineda-Roman M, Leukemia 2008; 22: 1419–1427.

22. Quach H, et al. Leuk Lymphoma 2009; 50: 223–229.

23. Mellqvist UH et al. Blood 2013;121:4647-4654

Paiva et al. Leukemia 2013 (epub ahed of print)

Unbalance ratio in favor of clonal PCs

MGUS-like signature (symptomatic MM)

(N = 59)

Symptomatic MM

(N = 639) Higher BM

tumor burden

P = .812

CR (n=26) < CR (n=33)

Outcome of symptomatic MM with an MGUS-like

signature independent of depth of response

TTP

Median: Not reached

Median: Not reached

140 120 100 80 60 40 20 0

100

80

60

40

20

0

Time from diagnosis (months)

Identical results by GEP in Total Therapy protocols Zhan et al. Blood. 2007;109:1692-1700




• Some patients in CR relapse early on








4. Galli M, et al. 2005; 90: 1643–1649.








12. Gay F, et al. Blood 2011; 117: 3025–3031.












Importance of achieving durable complete response (Results from TT2*)

Barlogie et al. Cancer 2008;113:355–359

SUS-CR:achieved and

sustained

CR status

NON-CR:never achieved

CR status

LOS-CR:attained

and lost

CR status

Survival by 3 year CR

Years from 3 years from enrollment 0 2 4 6

0%

20%

40%

60%

80%

100%

P value: a v b<0.0001, b v c <0.0001, a v c <0.0001

SUS-CR 28/256 NR

NON-CR 63/211 5.6 (4,6)

LOS-CR 23/39 1.6 (1,2)

*Total therapy 2 regimen: Induction: VAD, DCEP, CAD, DCEP

(TT2) Double transplantation: MEL 200 x 2

Consolidation: DCEP vs DCEP/CAD

Maintenance: Interferon

Randomization: thalidomide throughout vs no

thalidomide

Deaths/N Median in years





• Similar CR rates are associated with different outcome

• Different CR rates do not translate into different outcome








4. Galli M, et al. 2005; 90: 1643–1649.








12. Gay F, et al. Blood 2011; 117: 3025–3031.












Palumbo et al. EHA 2011 (oral presentation; plenary session)

CR: 25%

CR: 20%

P =.49

Similar results presented at the IMW2013 comparing CyRD vs. HDT/ASCT

Gay, F et al. IMW 2013 Abstract 7 (oral presentation; plenary session)





• Similar CR rates are associated with different outcome

• Different CR rates do not translate into different outcome








4. Galli M, et al. 2005; 90: 1643–1649.








12. Gay F, et al. Blood 2011; 117: 3025–3031.












Superior CR rates, but no differences in survival

MRC Myeloma IX trial (non-intensive)

Morgan GJ, et al. Blood. 2011 Aug 4;118(5):1231-8.

GIMEMA 26866138-MMY-3006

Cavo M, et al. Blood. 2012;120(1):9-19

R

Induction

HDT/ASCT R

Consolidation

Yes

No

Maintenance

Yes

No

R

R

Active drug

Placebo

Experimental

Standard

R

• Kinetics of response rather than a single assessment are more meaningful

• Historical landmark analysis do not take into consideration subsequent treatment strategies

• The most informative response assessments take place at the latest stages of treatment

• Ultimately, it needs to be really sensitive REDEFINE CR CRITERIA

Can single snapshot CR (or any depth-of-response)

assessment produce a miracle?

Re-defining the CR criteria in MM

Cellular clonality Cellular production Cellular dissemination

• Immunohistochemistry

• Flow cytometry

• ASO-PCR

• NGS

• sFLC

• Hevylite

• Isotype specific LC-MS/MS

• PET/CT

• WB-MRI

< 5% PCs in

bone marrow

Negative IFE of

serum and urine

Disappearance of soft

tissue plasmacytomas

Monitoring disease with PET/CT and WB-MRI

• PET/CT retained prognostic relevance also in

patients achieving CR (positive in 23%) 1

• MRD by WB-MRI was positive in 18% of patients

in CR, whereas MRI-CR was observed in 66% of

patients in PR (and in 33% of patients with

SD/PD). 2

• In how many patients in MRD is seen outside the

BM?

• Is the baseline imaging mandatory?

• Is there inter-observer reproducibility? 1,3

• False + (infection and/or inflammation) and false -

(high-dose steroids) results 4

1. Zamagni et al. Blood 2011;118(23):5989-95

2. Hillengass et al. Haematologica 2012; 97(11):1757-176

3. Moreau et al. Blood 2011;118(23): 5984-5985

4. Zamagni et al. Br J Haematol 2012;159: 499-513

PF

S A

ccord

ing to P

ET

-SU

V

Post-

AS

CT

PE

T/C

T in P

atients

Achie

vin

g C

R

1.00

0.75

0.50

0.25

0.00

0 12 24 36 48 60

PET-SUV 100%

reduction

30%

61%

Logrank P value=0.0195

Months

PET-SUV <100%

reduction




• Flow cytometry

• ASO-PCR

• NGS

• sFLC

• Hevylite


• PET/CT

• WB-MRI

< 5% PCs in

bone marrow

Negative IFE of

serum and urine



HLC ratios after treatment correlate with survival in

symptomatic multiple myeloma

Ludwig et al. Leukemia 2013;27(1):213-9.

All patients Patients in ≥ PR Patients in ≥ VGPR

• Early monitoring (after 2 cycles) of HLC patterns is an independent predictor of rapid response Bhutani M, et al. Blood 2013;122( 21): abstract 762

• HLC ratio as a surrogate marker of immune recovery after myeloablative transplantation, rather

than as a marker of minimal residual disease Tovar N, et al. Biol Blood Marrow Transplant. 2012;18(7):1076-9.

Does the stringent CR criteria represent a deeper

level of remission as compared to conventional CR?

• TTP in 115 patients in CR after induction (PETHEMA GEM05≥65 & GEM05<65 trials)

80 70 60 50 40 30 20 10 0

100

80

60

40

20

0 P=.190


80 70 60 50 40 30 20 10 0

100

80

60

40

20

0

P=.80

Time from diagnosis (months) Time from diagnosis (months)

80 70 60 50 40 30 20 10 0

100

80

60

40

20

0 P<.001

stringent CR

conventional CR

normal FLC

abnormal FLC

2-color FCM (IHC) -

2-color FCM (IHC) +

Martinez-Lopez et al; IMW 2013 (Abstract 415); poster presentation

Importance of achieving stringent CR

after ASCT in multiple myeloma

• Fully defined stringent CR using sFLC+IHC discriminates different outcomes among

patients in CR

Kapoor P et al. J Clin Oncol 2013;31:4529-35




• Flow cytometry

• ASO-PCR

• NGS

• sFLC

• Hevylite


• PET/CT

• WB-MRI

< 5% PCs in

bone marrow

Negative IFE of

serum and urine



Kappa probe X200

Lambda probe X200

IHC for the detection of (minimal?) residual disease?

Trephine biopsy: BM clonality is defined when the Κ/λ ratio is >4:1 or <1:2 for Κ and λ

patients, respectively, after counting ≥100 PCs

- BM biopsies is not a world-wide standard procedure

The majority of Κ/λ ratios after chemotherapy are polyclonal,

and clonality can only be detected after identification of

phenotypically aberrant cells

Normal PCs

Clonal PCs

MRD monitoring by NGS - superior applicability and sensitivity -

• Among CR (n=62), NGS discriminated two risk groups with different TTP (131 vs 35months, P <0.001) but

no differences for overall survival (both medians NR, P =0.1)

• Similar results for TTP/OS obtained by 4-color flow cytometry

• NGS+ MFC- patients have inferior TTP (P =.048) compared to NGS- MFC- cases

Martinez-Lopez J, et al. Blood 2013;122: abstract 1848

MRD monitoring by 4-color flow: patients >65y

Median: NR

Median: 29m

P =.049

Flow CR (n=24) MRD positive (n=20)

Time from MRD assessment (months)

• 44 patients in CR after induction therapy (GEM2005MAS65)

TTP OS

Both medians NR

P =.145


100 90 80 70 60 50 40 30 20 10 0

100

80

60

40

20

0

100 90 80 70 60 50 40 30 20 10 0

100

80

60

40

20

0

Paiva B et al; J Clin Oncol. 2011;29(12):1627-33. (f/u updated March 2014)

MRD monitoring by 4-color flow: patients <65y

Median: 50m

Median: 27m

P =.001



• 102 patients in CR after HDT/ASCT (GEM2005NENOS65)

TTP OS

Both medians NR

P =.21


90 80 70 60 50 40 30 20 10 0

100

80

60

40

20

0

90 80 70 60 50 40 30 20 10 0

100

80

60

40

20

0

Paiva et al. Blood 2010. 116; abstr 1910 (f/u updated April 2014)

Rawstron A, et al. J Clin Oncol. 2013;31(20):2540-7.

p-value for logrank test = .0018

1.0

0.8

0.6

0.2

0.4

0.0

0.9

0.7

0.5

0.1

0.3

0 24 48 72 6 12 18 30 36 42 54 60 66

PFS

• 214 patients in CR after HDT/ASCT (MRC myeloma IX)




Non-significantly inferior OS

(median 61.9 months vs. not reached; P =.0928)

Why is it so difficult to see differences on OS?

Flow CR (n=111)

MRD positive (n=121)

(GEM2005MENOS65) 232 patients tested for MRD (GEM2005MAS65) 153 patients tested for MRD

OS

P =.003


100 90 80 70 60 50 40 30 20 10 0

100

80

60

40

20

0

Flow CR (n=34)

MRD positive (n=119)

OS

Both medians: NR

P =.017


Both medians: NR

90 80 70 60 50 40 30 20 10 0

100

80

60

40

20

0


Median: 61m

Median: 62m

P < 0.001 P < 0.001 Median: 36m

Median: 141m

160 140 120 100 80 60 40 20 0

100

80

60

40

20

0

140 120 100 80 60 40 20 0

100

80

60

40

20

0

• 125 patients in CR after HDT/ASCT (GEM2000)

TTP OS


Paiva B et al; Blood. 2008; 15;112(10):4017-23 (f/u updated July 2012)




• Flow cytometry

• ASO-PCR

• NGS

• sFLC

• Hevylite


• PET/CT

• WB-MRI

< 5% PCs in

bone marrow

Negative IFE of

serum and urine



How to choose?

0 1 2 3 4 5 6 7 8 9

stringent CR 1

Flow cytometry 2-9

ASO-PCR 8,10,11

NGS 9

PET/CT 12

PFS OS

Published/reported data EXCLUSIVELY among

patients in CR

1. Kapoor P et al. J Clin Oncol 2013;31:4529-35

2. Rawstron AC, et al. Blood 2002; 100(9):3095-3100

3. Paiva B et al; Blood. 2008; 15;112(10):4017-23

4. Paiva B et al. Blood 2010;116: abstract 1910

5. Paiva B et al; J Clin Oncol. 2011;29(12):1627-33

11. Corradini P, et al. Blood. 2003;102:1927-1929

12. Zamagni et al. Blood 2011;118(23):5989-95

6. Paiva B, et al. Blood. 2012;119:687-91.

7. Rawstron A, et al. J Clin Oncol. 2013;31(20):2540-7.

8. Puig N et al. Leukemia. 2013. doi: 10.1038/leu.2013.217

9. Martinez-Lopez J, et al. Blood 2013;122: abstract 1848

10. Martinelli G, et al. J Clin Oncol 2000;18:2273-2281

Unmet need to consistently go beyond 10-5

200.000 events 2.000.000 events > 4.000.000 events

MRD+ve: 0.001% (10-5)

GEM2010 GEM2012 GEM2000/GEM2005

Higher sensitivity uncovers the unmeet need for

higher resolution

Polyclonal

Clonal

% o

f tu

mor

cells

0

1 10-1 10-2 10-3 10-4

Background

Protein

• monoclonal vs. oligoclonal sPEP

• atypical abnormal sFLC ratios

Imaging • false + (infection; inflammation)

• false - (high-dose steroids)

Cellular

• new “normal” phenotypes

• disproportional amplification of

different rearrangements

Standardization of multidimensional flow cytometry to

implement Flow-CR as a clinical end-point

Normal PC

reference

Myeloma PC

reference

• Software guided PC identification and computerized classification of normal vs. aberrant PCs

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&docid=WxrOmQ1eCPORLM&tbnid=w-uVvzAwohDFdM:&ved=0CAUQjRw&url=http://myeloma.org/Main.action/..pdfs/SGLTools/pdfs/store/IndexPage.action?tabId%3D0%26menuId%3D0%26indexPageId%3D1%26page%3D5%26pageAction%3Dnext%26parentTabId%3D0%26parentLinkId%3D0%26parentMenuItemId%3D0%26parentNuggetId%3D1%26parentKeywordId%3D0&ei=yyL4Us3hGKmW0QWnyIDQBQ&bvm=bv.60983673,d.d2k&psig=AFQjCNG8cy-57yDUUm8Ej2pJkK82mIiAJA&ust=1392079877616612

• Can imaging- or NGS- based MRD monitoring be performed w/o baseline evaluation?

CLL/MBL-like clone in

~5% of MM patients

Paiva B, et al. unpublished observations

Do I have available baseline sample/studies?

Ig sequencing

In which patients and where should

MRD be investigated?

140 120 100 80 60 40 20 0

100

80

60

40

20

0

Standard-risk / MRD- (n=88)

High-risk / MRD- (n=82)

Standard-risk / MRD+ (n=119)

High-risk / MRD+ (n=25)

GEM2000+GEM2005<65y: Impact on survival of achieving immunophenotypic CR according to cytogenetics

PFS

Standard-risk / MRD- vs Standard-risk / MRD+; P < 0.001

vs High-risk / MRD-; P =.462

High-risk /MRD- vs Standard-risk / MRD+; P=.135

vs High-risk / MRD+; P = 0.001

Identical results in the MRC myeloma IX study Rawstron A, et al. J Clin Oncol. 2013;31(20):2540-7.

Where could Flow-CR be clinically relevant?

Pretreatment prognostic factors

MRD

Induction TD TD TD

HDT/ASCT

Consolidation

Not all patients in CR after induction look the same

at the MRD level

Median: 85m

Median: 10m

P =.001

Flow CR (n=6)

MRD positive (n=16)


• 22 patients in CR after HDT/ASCT:

monitoring stem cell harvests

TTP MRD (-) MRD (-)

MRD (+) MRD (-)

MRD (+) MRD (+)

P =.84

• PFS: GEM2000 & GEM2005<65y

(patients in CR after induction)

140 120 100 80 60 40 20 0

100

80

60

40

20

0

Paiva B, et al. (unpublished)


TTP

Similar results by PCR: Takamutsu H, et al. Exp Hematol. 2013;41(10): 894-902

140 130 120 110 100 90 80 70 60 50 40 30 20 10 0

100

80

60

40

20

0


MRD

Induction TD TD TD

HDT/ASCT TD

Consolidation

Maintenance

F/up


Progression-free survival by 100-day outcome assessed in all patients by MRD/maintenance; T: thalidomide; NM: no

maintenance

p-value for logrank test = 0.036

Pro

po

rtio

n e

ven

t fr

ee

1.0

0.8

0.6

0.2

0.4

0.0

0.9

0.7

0.5

0.1

0.3

0 24 48 72 6 12 18 30 36 42 54 60 66

T; MRD+ NM; MRD+

MRC myeloma IX trial: What about maintenance

therapy after HDT/ASCT?

Rawstron A, et al. J Clin Oncol. 2013;31(20):2540-7.

Maintenance alone did not overcome unsustained CR

TTP after day+100 HDT/ASCT

P <.001 P <.001

Median: NR

Median: 83m

Median: 28m

80%

94%

Standard-risk FISH + MRD negative (n=58)

High-risk* FISH OR MRD positive (n=45)

High-risk* FISH + MRD positive (n=7)

0%

Median: 6m

1y

Median: 47m

Median: 21m

100 90 80 70 60 50 40 30 20 10 0

100

80

60

40

20

0

42%

89%

2.5y

76%

5y

OS after day+100 HDT/ASCT

100 80 60 40 20 0

100

80

60

40

20

0

Paiva B, et al. Blood. 2012;119:687-91.

Months Months

* t(4;14), t(14;16) and/or del(17p)


MRD

Induction TD TD TD

HDT/ASCT TD

Consolidation TD

Maintenance

F/up

F/up


Impact of MRD after consolidation with VTD

Ladetto M et al. J Clin Oncol. 2010;28:2077.

Ladetto M et al. Blood. 2011;118: Abstract 827.

Patients: (n=39) with ≥VGPR after consolidation


MRD

Induction TD TD TD

HDT/ASCT TD

Consolidation TD

Maintenance TD

F/up

F/up TD

TD

Preventive

treatment


Treatment prolonged until MRD clearance or stabilization (plateau)

“Continuous treatment“ “consolidation/maintenance” (+/- 4 or 6 m)

and stop

Can we turn myeloma into CML?

R

Can we turn myeloma into CML?

• Immunophenotypic relapse anticipate clinical relapse 1

• There is a 9 months lag between molecular CR loss and need for salvage treatment 2

• Flow cytometry permits the detection of MRD preceding frank relapse 3

• A dynamic increase in molecular tumor burden detectable by RQ-PCR, predicts late

disease relapses several months before clinical recurrence 4

• Should these patients be re-treated (e.g.: MoAb±IMiD?) 1. Rocci A et al. Blood 2013;122: abstract 3126

2. Ferrero S et al. Blood 2013;122: abstract 2077

3. Kosuri S et al. Blood 2013;122: abstract 4647

4. Ladetto M et al. Blood 2011;118: abstract 827

31 patients in CR + Flow CR

after up-front treatment

MRD monitoring

during f/up MRD positive:

85% clinical relapse

Flow CR:

39% clinical relapse

P =.01

Paiva B et al. manuscript ijn preparation


MRD

Induction TD TD TD

HDT/ASCT TD

Consolidation TD

Maintenance TD

F/up

F/up TD

TD

Preventive

treatment

Salvage

treatment

Relapse

TD


150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0

100

80

60

40

20

0

Median: 25m

Median: 13m

P =.035



• 43 patients in CR after salvage therapy (81% treated w/o novel agents; 63% received SCT)

TTP OS

Median: NR

Median: 38m

P =.221


Myeloma-related deaths: 103m vs. 41m (P =.05)

BSBMT/Ukmf Myeloma X (patients in CR after salvage therapy) TTP: 25 vs. 10m (P <.001) Ashcroft J et al; Blood 2013;122 (21): abstract 3378

140 130 120 110 100 90 80 70 60 50 40 30 20 10 0

100

80

60

40

20

0

Paiva B. et al. EHA 2013; abstract P219; median f/up: 16 months

MRD monitoring by 4-color flow: R/R patients

125 100 75 50 25 0

100

80

60

40

20

0

OS

P < 0.001


• Standard-risk (80%): 6-8 years median OS

• High-risk (20%): 2-3 years median OS - t(4;14)

- t(14;16)

- del(17p)

- GEP signature

• Many novel agents being developed - monoclonal antibodies

- deacetylase inhibitors

- many more…

• Wait 8-years to demonstrate improvement in OS

of standard-risk patients?

• Wait for early dead to demonstrate lack of

improvement OS in high-risk patients?

Where else can MRD be of help in MM?

140 120 100 80 60 40 20 0

100

80

60

40

20

0

PETHEMA/GEM & MRC: same PFS independent of previous induction regimen

GEM2000: MRD - (n=71)

MRD + (n=54)

PFS

Medians: 62m & 59m P =.21

Medians: 36m & 39m P =.90


GEM2005<65y: MRD - (n=68)

MRD + (n=34)

Rawstron A, et al. IMW 2013 Abstract 16 (oral presentation; plenary session)

Paiva et al. Blood 2010. 116; abstr 1910. (updated July 2012)

PFS

State of the art therapy should go along with state

of the art response criteria

Year 1998 2006 2011 2013 2014

Criteria EBMT (Blade) 1 IMWG 2 IMWGv2 3 ?

Depth of

response CR Stringent CR

Flow CR

Molecular CR

Flow CR

Molecular CR

NGS CR

PET/CT

Flow CR

NGS CR

Imaging CR

Thalidomide

Lenalidomide

Bortezomib Carfilzomib

Pomalidomide

HDT/ASCT MoAbs??

Documents

Bruno Paiva University of Navarra, Spain - Comtecmed · Bruno Paiva University of Navarra, Spain 1st World Congress on Controversies in Multiple Myeloma. Bangkok, Thailand. May 11-13