Mayo Clinic College of MedicineMayo Clinic Comprehensive Cancer Center

New IMWG Response CriteriaShaji Kumar, M.D.

Professor of MedicineDivision of Hematology

Mayo Clinic

Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida

Limitations of current criteria

Response depth and outcome

CR, complete response; MR, minor response; MRD, minimal residual disease; nCR, near complete response;

PR, partial response; sCR, stringent complete response; VGPR, very good partial response

CRnCR

VGPRPRMR

Time to disease progression

Diagnosis

Dep

th o

f res

pons

e

sCRCure?

Therapy and depth of response

Stewart KA, et al. Blood 2009;114:5436–43; Jakubowiak AJ, et al. Blood 2012;120:1801–9.

CR, complete response; CVD, cyclophosphamide, bortezomib, and dexamethasone; CVRD, bortezomib, dexamethasone, cyclophosphamide and lenalidomide; KRd, carfilzomib, lenalidomide and dexamethasone; nCR, near complete response; ORR, overall response rate; PAD, bortezomib, doxorubicin, and dexamethasone; PR, partial response; RD, lenalidomide and dexamethasone; RVD, lenalidomide, bortezomib and dexamethasone; sCR, stringent complete response; TD, thalidomide and dexamethasone; VAD, vincristine, doxorubicin and dexamethasone; VGPR, very good partial response; VTD, bortezomib, thalidomide, and dexamethasone

97

72

55

39

0

20

40

60

80

100

120

PR VGPR CR sCRPr

opor

tion

KRd

ORRVGPRCR/nCR

0

20

PR

40

60

80

Perc

enta

geVGPR CR sCR

100

0

20

VAD

40

60

80

Perc

enta

ge

RD VTD RVD

100

TD PAD CVD CVRDInduction regimen

Transitioning from conventional CR

Complete Response (CR)

• Negative serum and urine immunofixation

• <5% PCs in marrowStringent Complete Response (sCR)

• Normal FLC ratio• No clonal plasma cells in marrow

MRD negative

• Flow negative MRD• Sequencing negative MRD• Imaging negative MRD

How do we define MRD negativity?The tools:

• Flow cytometry

• NextGen sequencing

• Imaging

Depth of response and outcome

Martinez-Lopez J, et al. Blood 2014;123:3073–9.

PFS OS

0

20

0 50

Median: 80

150

40

60

80

100

Tim

e to

pro

gres

sion

(%)

Time (months)

Median: 45

Median: 27

0.003

0.002<0.001

100

MRD– <10-5 (n=30)MRD+ 10-3–10-5 (n=37)MRD+ >10-3 (n=43)

0

20

0 50

Median: NR

150

40

60

80

100

Surv

ival

(%)

Time (months)

Median: NR

Median: 55

0.3

0.020.002

100

NR, not reached; OS, overall survival; PFS, progression free survival

Deeper response… better outcome

Rawstron AC, et al. Blood 2015;125:1932–5.

0

20

0 1 6

40

60

80

100

Prog

ress

ion-

free

sur

viva

l (%

)

Time (years)42 3 5 7 8 9

0

20

0 1 6

40

60

80

100

Ove

rall

surv

ival

(%)

Time (years)42 3 5 7 8 9

<0.01% (N=247)0.01–<0.1% (N=49)0.1–<1% (N=72)1– 10% (N=26)≥10% (N=3)

MRD after novel combinations

VRD induction VRD or HDT consolidation VRD consolidation Len maintenance for 1 year

Avet-Loiseau et al. Blood 2015;126:191.

P-value : p<0.0001

Negative (<10-6)

Positive

P-value : p<0.0001

Negative (<10-6)

Positive

0.0

0.2

0 6 36

0.4

0.6

0.8

1.0

Time since randomization (months)2412 18 30 42 48

P<0.0001

Positive

Negative (<10-6)

MRD at pre-maintenance

0.0

0.2

0 6 36

0.4

0.6

0.8

1.0

Time since randomization (months)2412 18 30 42 48

P<0.0001

Positive

Negative (<10-6)MRD at post-maintenance

HDT, high-dose therapy; Len, lenalidomide; VRD, bortezomib, lenalidomide and dexamethasone

Patie

nts w

ithou

t pro

gres

sion

(%)

Role of imaging

Elena Zamagni et al. Blood 2011;118:5989-5995

©2011 by American Society of Hematology

Post-induction PET

Elena Zamagni et al. Blood 2011;118:5989-5995

©2011 by American Society of Hematology

Post ASCT PET

p < 0.001

69%

51.6%

PET-CT normalisation Pre-maintenance: PFS

p = 0.003

94.6%

69.9%

PET-CT normalisation Pre-maintenance: OS

p = 0.02

89.6%

54.5%

PET and Flow negative: PFS

Durability of response

Hoering A, et al. Blood 2009;114:1299–305.

0

20

0 2

40

60

80

100

Years from 3-year landmark after enrolment4 6

TT2 overall survival by 3-year CR statusPe

rcen

tage

8

P-values:a vs b <0.001a vs c <0.001b vs c <0.001

Deaths/N 5-year estimate (%)a) sus–CR 38/258 82b) non–CR 78/218 59c) los–CR 27/37 24Log-rank P-value <0.0001

Revised IMWG response criteriaResponse

subcategoryResponse criteria

IMW

G M

RD n

egat

ivity

crit

eria

(R

equi

res

com

plet

ere

spon

se a

s orig

inal

ly d

efin

ed)

Sustained MRD-negative

MRD –ve in the marrow (next-generation flow cytometry [NGFC] and/or next-generation sequencing [NGS]) and by imaging as defined below, confirmed one year apart. Subsequent evaluations can be used to further specify the duration of negativity

Flow MRD-negative

Absence of phenotypically aberrant clonal plasma cells by NGFC on bone marrow aspirates using the EuroFlow standard operation procedure for MRD detection in MM (or validated equivalent method) with a minimum sensitivity of 1 in 105 nucleated cells or higher

Sequencing MRD-negative

Absence of clonal plasma cells by NGS on bone marrow aspirates in which presence of a clone is defined as less than two identical sequencing reads obtained after DNA sequencing of bone marrow aspirates using the Lymphosight® platform (or validated equivalent method) with a minimum sensitivity of 1 in 105 nucleated cells or higher

Imaging + MRD-negative

MRD negative as defined by NGF or NGS PLUS Disappearance of every area of increased tracer uptake found at baseline or a preceding PET/CT or decrease to < mediastinal blood pool SUV or decrease to less than that of surrounding normal tissue

CT, computed tomography; IMWG, International Myeloma Working Group; MM, multiple myeloma; PET, positron emission tomography; SUV, standard uptake valueKumar S, et al. Lancet Oncol; in press.

Endpoints

Endpoint DefinitionTTP Duration from start of treatment to disease progression, with deaths from causes

other than progression censored.PFS Duration from start of the treatment to disease progression or death (regardless

of cause of death), whichever comes first.EFS The definition for EFS depends on how “event” is defined. In many studies, the

definition of EFS used is the same as PFS. EFS may include additional “events” that are considered to be of importance besides death and progression, including serious drug toxicity.

DFS Duration from the start of MRD negativity to the time of reappearance of MRD. DFS applies only to patients in MRD negative state.

DOR Duration from first observation of PR to the time of disease progression, with deaths from causes other than progression censored.* Duration of MRD, CR and PR should each be reported as appropriate.

Questions