Percorsi diagnostico-terapeutici nel

Mieloma Multiplo

nella regione Liguria

Genova

28 Novembre

20182018

NUOVI CRITERI DIAGNOSTICI E

PROGNOSTICI NEL MIELOMA MULTIPLO

Elena Zamagni

“Seràgnoli” Institute of Hematology

Bologna University School of Medicine

DRUGS DEVELOPMENT IN MULTIPLE MYELOMA

< 3 g/dL serum

AND

MonoclonalGammopathy of

uncertain significance(MGUS)

Present(serum/urine)

AND

SymptomaticMultipleMyeloma

≥ 3 g/dL serum

AND/OR

Smoldering Multiple

Myeloma (SMM)

Monoclonal component

Classification of monoclonal gammopathies

AND

< 10%

AND

Absent

> 10%b

AND

Present

10-60%

AND

Absent

Bone MarrowPlasma Cells (%)

Mieloma-defining event (CRAB)

Concomitant diseases that can mimic MM:-Increase of serum Cr due to diabetes or hypertension-Anemia due to idon-vitamin deficiency, chronic disease,..

-Diffuse osteoporosis-Hyperparatiroidism-Single asymptomatic bone lesion

Kyle RA, IMWG, BJH 2003

Absent

REVISED IMWG DIAGNOSTIC CRITERIA

Rajkumar V et al, Lancet Oncol 2014

Wester R and Sonneveld P Haematologica 2016;101(5):518-20.

IMWG MRD criteria

Response SubCategory Response Criteria

Sustained MRD-negative MRD negativity in the marrow (NGF or NGS, or both) and by imaging as

defined below, confirmed minimum of 1 year apart. Subsequent evaluations

can be used to further specify the duration of negativity (eg, MRD-negative

at 5 years)†

Flow MRD-negative Absence of phenotypically aberrant clonal plasma cells by NGF‡ on bone

marrow aspirates using the EuroFlow standard operation procedure for MRD

IMWG MRD negativity criteria

(requires a complete response)

marrow aspirates using the EuroFlow standard operation procedure for MRD

detection in multiple myeloma (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 aspirate 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 positive

MRD-negative

MRD negativity 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 less mediastinal blood pool SUV or decrease to less than that of

surrounding normal tissue

Kumar SK, et al. Lancet Oncology 2016;17(8):e328-e346

Transition from MGUS/SMM to MM

Genetic events: genetic instability, accumulation of abnormalities

Epigenetic events

Clonal selection: expansion of altered clones already present in MGUS

Permissive microenvironment

Ghobrial I et al, Blood 2014

Ahn IE et al, JCO 2015

Bianchi G et al, Blood 2015

Permissive microenvironment

Reduction of immune surveillance

MGUS: Evolution in whom and at what rate?

However, majority doesnot develop MM

MGUS 1%/year

Kyle RA et al. NEJM 2007Proposed risk factors:

-Monoclonal-(M)-spike 1.5 g/dl or higher

-Skewed FLC-ratio (ref 0.26-1.65)

-Immunoparesis

-Non-IgG M-spikeLandgren O et al. Clin Cancer Res 2011

Kyle RA et al, NEJM 2018

MGUS 1%/year

SMM: Heterogeneus disease

3%/year from 5-10 years1%/year thereafter

Perez-Persona E, et al. Blood. 2007;110:2586-92.

10%/year

PROGNOSTIC FACTORS OF PROGRESSION IN SMM

• MC concentration (cut-off 3 g/dL)

• Changes in MC over time (“evolving pattern”): progressive increase of atleast 10% in the first 6 months if initial MC > 3g/dL or progressive annualincrease within 3 years if MC < 3 g/dL

• FLC ratio alteration

• BM plasma cells

• MRI FLs• MRI FLs

• Immunoparesis

• Presence of Proteinuria, in particular if > 500 mg/24h (NO PROGNOSTICVALUE OF BJ POSITIVITY!)

• Aberrant BM PCs phenotype

• Cytogenetic abnormalities

Rajkumar V et al, Blood 2005

Gonzalez de la Calle et al, Leukemia 2016

Rosinol L et al, Mayo Clinic Proc 2007

Dhodapkar MV et al, Blood 2014

Kyle R et al, NEJM 2007

Vd Donk et al. Haematologica 2014;99:984-996

Fernández Larrea C et al. ASH 2014

Ultra-high risk SMM

Use the higher value if discrepancy between

BM aspiration and biopsy

Median TTP: 55 m

Median TTP: 15 m

Median TTP: 7 m

1. Rajkumar SV et al. N Engl J Med 2011; 365:474-475

2. Kastritis E, et al. Leukemia. 2013 Apr;27(4):947-53

3. Waxman AJ, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 8607)

4. Larsen JT at al, Leukemia 2013

5. Hillengass J, et al. J Clin Oncol 2010;28:1606-1610

6. Kastritis E, et al. Leukemia. 2013 Apr;27(4):947-53

Median TTP: 13 m

Median TTP: NR

Pro

gres

sion

-fre

e su

rviv

al

Time since MRI Treatment (months)

1.0

60 1812 3024 4236 5448 60

0.8

0.6

0.4

0.2

0

> 1

Log-rank p < 0.001

Whole MRI: FLs

PROGNOSTIC VALUE OF WBMRI: IMPORTANCE OF FOLLOW-UP

Critical evaluation of doubt lesions!

REVISED IMWG DIAGNOSTIC CRITERIA: BIOMARKERS OF MALIGNANCY

Rajkumar , Lancet Oncol 2014

Definition of high risk SMM

RajKumar V S et al, Blood 2015

Smoldering Multiple Myeloma: prognostic factors

Evolution pattern of the M-spike: evolving vs non evolving (n:206)

• Evolving SMM (25%): at least 10% increase in the M-protein size within the first 12months from diagnosis when baseline M- protein was ≥ 30 g/L or progressive increasein MP in each of the annual consecutive measurements during a period of 3 years inpatients with an initial MP < 30 g/L

• Non-evolving (75%): Stable serum M-protein until progression occurs

Evolving SMM

• Risk progression at

Pro

babi

lity

of p

rogr

essi

on

• Risk progression at 2 years: 45%

• Risk progression at 5 years: 78%

• IgA isotype: 38% vs.

24%; p=0.061

Fernández Larrea C et al. Leukemia. 2018

Pro

babi

lity

of p

rogr

essi

on

Evolving SMM

Non-evolving SMM

Smoldering Multiple Myeloma: prognostic factors

Bence Jones proteinuria in SMM as a predictor marker of progression to symptomatic MM

González- Calle V et al. Leukemia 2016

• del(17p13), t(4;14), +1q21 showed significant impact on TTP

TTP P

All pts 4.9 years

+1q21 versus no gain of 1q21 3.7 years 5.3 years 0.013

del(17p13) versus no del(17p13) 2.7 versus 4.9 years 0.019

Del(17p), t(4;14), and +1q21 predict progression from smoldering to symptomatic MM (n=248)

Smoldering Multiple Myeloma: prognostic factors

• Multivariate analysis: t(4;14), +1q21, HD, reduction of uninvolved immunoglobulins and risk score defined by Kyle et al. as independent factors for adverse outcome

• Conclusion: specific chromosomal aberrations drive transition from asymptomatic to symptomatic disease

t(4;14) versus no t(4;14) 2.9 versus 5.2 years 0.021

HD versus NHD 3.9 versus 5.7 years 0.036

Neben et al. JCO 2013

� No uniform accepted definition of high-risk or intermediate-risk SMM1

% Progressing to Symptomatic MM

Mayo Clinic2

3 Criteria:1/3 Criteria(Low risk)

2/3 Criteria(Intermediate

risk)

3/3 Criteria(High risk)

1. M-protein ≥3 g/dL2. ≥10% clonal bone

marrow plasma cells 25% 51% 76%

Risk models for the stratification of SMMSmoldering Multiple Myeloma: prognostic factors

marrow plasma cells3. Free light-chain

<0.125 or >8

25% 51% 76%

PETHEMA3

2 Criteria:0/2 Criteria(Low risk)

1/2 Criteria(Intermediate

risk)

2/2 Criteria(High risk)

1. ≥95% abnormal plasma cells

2. Low uninvolved serum immunoglobulins

4% 46% 72%

1. Rajkumar SV, et al. Blood. 2015;125(20):3069-3075;2. Dispenzieri A, et al. Blood. 2008;111(2):785-789; 3. Pérez-Persona E, et al. Blood. 2007;110(7):2586-2592.

TTP 1,9 yTTP: 5 yTTP 10 y

IMF Smoldering Multiple Myeloma (SMM) retrospective chart review

New Paradigm for SMM: risk-adapted approach

Low Risk

Smoldering Myeloma (14%)*

Stratification according to risk of progression

Intermediate Risk High Risk

Ultra-high risk (5-10%) =

MM

Kristinsson S Y et al NEJM 2013Ghobrial I et al, Blood 2014 Rajkumar V et al, Blood 2015 *Using the Swedish Myeloma registry, 2494 pts from 2008 to 2011

Low Risk(40%)

• TTP 25% at 5 yrs• Follow up as

MGUS (6-12 mos)

Intermediate Risk(30%)

High Risk(30%)

• TTP 50% at 5 yrs• Close follow up

every 3-6 months

• TTP 70% at 5 yrs• Candidates for clinical

trials (early treatment)

High-risk SMM seems to benefit from therapy. However, there are still fundamental questions for which wedo not yet have clear answers:

• What is the most appropriate treatment?

Shall we treat smoldering multiple myeloma in the near future?Ola Landgren

2017

Clinical trials and long term follow-up are needed to address these important questions

• What is the most appropriate treatment? • Instead of using powerful 3-drugs therapy, is it enough to use more gentle therapy (eg, a 2-drug combination)?• What is the optimal duration?• In case of a recurrence, can therapy be resumed with the same efficacy?

SMM: future directionsCurrent paradigm Proposed future directions

High-risk SMM MM (early detection)

Intermediate-risk SMM Indolent MM

Low-risk SMM Monoclonal gammopathy

Landgren O, ASH 2017

Dispenzieri A, Blood 2014

IMWG: M-protein, bone marrow plasma cells, and

organ impairment define plasma cell disorder

• < 10% BMPC AND

• < 3 g/dL M protein AND

• No MDE

• ≥ 10% to 60% BMPC OR

• ≥ 3 g/dL serum M protein OR

• ≥ 500 mg/24 hr urine M protein AND

• No MDE

• PCPD, AND

• 1 or more MDE

o CRAB

o ≥ 60% BMPC

o ≥ 100 FLC ratio

MGUS SMM MM

Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

o ≥ 100 FLC ratio

o > 1 MRI focal lesion

MDE, myeloma-defining events

No MDE MDE

REVISED IMWG DIAGNOSTIC CRITERIA: from CRAB to slim- CRAB to MDE

MDE

Rajkumar , Lancet Oncol 2014

CRAB

• Definition of myeloma bone disease (CRAB):clear evidence of one or more sites of osteolytic bone destruction (at least 5 mm or more in size) seen on CT, WBLDCT, PET/CT, regardless of weather they can be visualized on skeletal radiography or not

REVISED IMWG DIAGNOSTIC CRITERIA: new definition of MDE

Bone disease

Rajkumar V. et al., Lancet Oncology 2014

• If doubt lesions on CT or PET/CT: close follow-up every 3-6 months and/or biopsy of the lesion

• Oseoporosis per se not attributable to myeloma is not sufficient for CRAB

SYSTEMATIC REVIEWNEW IMAGING TECHNIQUES HAD A HIGHER DETECTION

RATE AS COMPARED TO WBXR*

* Except for ribs and skull

Regelink JC et al. BJH 2013;162:50-61.

PET/CT neg (97 pts): 30% at 2 yrs

TTP TTP

PET/CT pos (74 pts): 75% at 2 yrs

P= 0.0008 P= 0.004

PET/CT neg: median 60 mos

PET/CT pos with osteolyses (16 pts): median 21 mos (87% at 2 yrs)

Siontis B. et al, Blood Cancer J 2015

Hillengas J et al. BCJ 2017

• Retrospective analysis of 212 pts with suspected SMM studied by WBXR and WBCT within 30 days• 25% higher sensitivity of WBCT (WBXR false negative)

WHAT IMAGING TO USE FOR STAGING?

WHAT IMAGING TO USE FOR STAGING?

WBLDCT PET/CT MRI

• Widely available

• Patient-friendly (fast scanningtime, < 15 min)

• Relatively low radiation dose (3-4mSv)

• Can contemporary depict lytic lesions and disease metabolism

• Prognostic significance of FLs and SUV

• Highest sensitivity for early bone damage

• No radiation exposure

• Prognostic significance of FLs and diffuse pattern

Choice usually made according to local clinical practice, resources, expertise and national guidelines

• Relatively cheap

• No need for iv contrastadministration

• Gold standard for CT-guided biopsy,surgery, RT planning, evaluation ofstability of fractures

• Comparison with post-treatment evaluation

• Gold standard to assess EMD

• Gold standard for detection of diffuse BM involvement, differential diagnosis between osteoporotic and pathological fractures, cord compression

•Definition of renal failure:

•measured or estimated glomerular filtration rates less than 40 mL/min (which

corresponds to about a 40% decrease from the lower limit of the normal glomerular

filtration rates) be used instead of a fixed serum creatinine concentration to fulfil the

CRAB criteria

REVISED IMWG DIAGNOSTIC CRITERIA: new definition of MDE

Laboratory

•the criteria have also been updated to clarify that only renal failure caused by light-

chain cast nephropathy (based on typical histological changes or presumptive

diagnosis based on the presence of high involved FLC levels, typically >1500 mg/L) is

regarded as a myeloma-defining events.

Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

Selective vs non selective

proteinuria

Dimopoulos MA et al (IMWG Consensus), J Clin Oncol 2016; 34:1544-1557MIDD, monoclonal Ig deposition disease.

DIAGNOSTIC EVALUATION

Myeloma Is Not One Disease

~ 25% pts dead in 3 yrs

Kumar SK, et al. Leukemia. 2014;28:1122-1128

> 50% ptsalive at 5 yrs

Prognostic factors in MM

Patient-related

• Age

• Performance status, comorbidities

Disease-related

• High β2 microglobulin

• Low albumin

• Renal impairment

ISSDisease burden

• Renal impairment

• LDH above the upper limit

• Cytogenetic abnormalities

• Gene expression profile

• Circulating plasma cells

• Extramedullary disease

• High proliferation rate

Therapy-related

• Quality of response

• Early relapse

Disease biology

Dynamic Model

At diagnosis

Why Risk Stratify?

• Two important goals

– Counsel: Need to provide pt with realistic expectations

based on the currently available treatments

– Therapy: Decide if particular therapies can be chosen

based on their differential effects on the high-risk and

standard-risk disease

Consensus statement

•Translocations t(4;14), t(14;16), t(14;20), and del(17/17p) and any nonhyperdiploid

karyotype are HR cytogenetics in NDMM regardless of treatment.

•Gain(1q) is associated with del(1p) carrying poor risk.

•Increased risk with increased number of lesions (DOUBLE HIT MM)

•Combinations of ≥3CA confer ultra-HR with <2 years survival.•Combinations of ≥3CA confer ultra-HR with <2 years survival.

•Routine testing should include t(4;14) and del(17p).

•Clinical classifications may combine these lesions with ISS, serum LDH, or HR gene

expression signatures.

Sonneveld P, et al.. Blood 2016; 127:2955-2962

High-risk Standard-risk

Cytogenetic

abnormality

FISH: t(4;14), t(14;16), t(14;20),

del(17/17p), gain(1q)

Nonhyperdiploid Karyotipe

Karyotype del(13)

GEP: high-risk signature

All others including: FISH: t(11;14), t(6;14)

Gene Expression–Based Classifications

Signatures

• GEP70• GEP17• HOVON• HOVON• IFM

Shaughnessy JD Jr, et al. Blood. 2007;109:2276-2284.

The International Staging System (ISS)Prognostic model based on β2-microglobulin and albumin

Patients < 65 y

Stage Criteria

Iβ2m < 3.5 mg/L

& albumin ≥ 3.5 g/dL

Patients > 65 y

II Not stage I or III

III β2m ≥ 5.5 mg/L

Greipp et al. J Clin Oncol 2005;23:3412-20

Prognostic factor Criteria

ISS stage

I Serum β2-microglobulin < 3.5 mg/L; serum albumin ≥ 3.5 g/dL

II Not ISS stage I or III

III Serum β2-microglobulin > 5.5 mg/L

High riskPresence of del(17p) and/or translocation t(4;14) and/or

Standard risk factors for myeloma and the R-ISS

A total of 3,060 pts with NDMM enrolled onto 11 international, multicenter clinical trials

All patients received new drugs (IMIDs or PIs)

CA, chromosomal abnormalities; iFISH, interphase fluorescent in situ hybridisation;

ISS, International Staging System; R-ISS, Revised International Staging System.

CA by iFISHHigh risk

Presence of del(17p) and/or translocation t(4;14) and/or

translocation t(14;16)

Standard risk No high-risk CA

LDHNormal Serum LDH < upper limit of normal

High Serum LDH > upper limit of normal

A new model for risk stratification for MM

R-ISS stage

I ISS stage I, standard-risk CA by iFISH and normal LDH

II Not R-ISS stage I or III

III ISS stage III and either high-risk CA by iFISH or high LDH

Palumbo A, et al. J Clin Oncol 2015;33:2863–9.

Revised ISS staging system

28%

62%

10%

Palumbo A, et al. J Clin Oncol 2015;33:2863–9.

OS @ 5yrs

82%

62%

40%

PFS @ 5yrs

55%

36%

24%

• High-risk can refer to many different characteristics and the magnitude of risk

can be influenced by different treatmens

• There is a lack of prospective randomized trials which might strongly support

choices of therapy in this settingchoices of therapy in this setting

• Management of high-risk MM includes a complicated set of steps requiring

an aggressive treatment approach

• The short-term goal of therapy is to achieve a rapid and complete response

and then to use different treatment strategies to further deepen the level of

response and maintain it below the detection level

Sonneveld P, et al.. Blood 2016; 127:2955-2962

Depth of response correlate with survivalMRD is the best biomarker to predict outcome

Lahuerta JJ, et al. JCO 2017;35(25):2900-2910 GEM2000 - GEM2005MENOS65 - GEM2010MAS65

Meta-analysis of MRD studies (CR patients) Munshi NC, et al. JAMA Oncol 2017;3(1):28-35

PFS

MRD negativity is a prognostic marker for PFS and OS

across the spectrum of patients with MM

OS

Lahuerta JJ, et al. JCO 2017;35(25):2900-2910

MRD SHOULD BE EVALUATED INSIDE AND OUTSIDE

THE BONE MARROW IN MULTIPLE MYELOMA

4

6

Rasche L et at, Nature Comm 2017 Growing heterogeneity with growing size of the lesions

FDG PET/CT FOR EVALUATION OF METABOLIC RESPONSE TO THERAPY AND MRD

both negative (47% pts)

either positive

COMPLEMENTARITY BETWEEN PET/CT AND BM FLOW CYTOMETRY*

Newly diagnosed transplant-eligible patients evaluated

4

7

Moreau P. et al, JCO 2017

patients evaluated pre-maintenance

*Sensitivity 10-4

• Who are the patients at risk of persistence of disease metabolism in FLs(imaging MRD positivity)?

• Those with EMD at diagnosis

• Those with para-skeletal disease

Patient 359 454 502 635 751 767

Diagnosis

ISS III III I III I I

1q+(50%) 1q+(85%) &

4

8

Relapse

M-protein - - + - - +

MRD (NGF, 10-

6)neg neg neg neg neg neg

Bone-relatedplasmacytomas

+ + + + NE +

FISH 1q+(59%) del17p(22%)1q+(50%)

& 1p-(61%)1q+(85%) &

1p-(89%)NE -

Bone-related plasmacytomas

+ + + + NE +

Paiva B et al, presented at ASH 2017

WHAT IMAGING TO USE AFTER TREATMENT?

PET/CT FUNCTIONAL MRI

• Results reproduced in large

prospective independent studies

• Higher reliability for diffuse BM

infiltration

• Early changes during treatment

4

9

• Prognostic significance in CR

patients (MRD monitoring) and

complementarity with bone

marrow techniques

• Small studies in heterogeneous

patient populations to date

PET/CT has the strongest recommendation to date

Table 6: Recommendations for use of 18F-FDG PET/CT in MM

Recommendation Grade

Active MM:

18F-FDG PET/CT can be considered as part of the initial workup in patients with newly diagnosed MM since itprovides information useful for prognostication and allows to more carefully assess the bulk of the disease,particularly in patients with extramedullary sites of the disease. This latter indication for use of 18F-FDG PET/CTapplies also to patients with relapsed/refractory MM

B

In newly diagnosed MM, EMD and >3 FLs on 18F-FDG PET/CT identify subgroups of patients with unfavorableoutcomes, particularly those who are candidates to receive upfront ASCT. Controversies exist about theprognostic role of SUVmax

B

18F-FDG PET/CT is by now the preferred technique for evaluating and monitoring response to therapy. Metabolicchanges assessed by 18F-FDG PET/CT provide an earlier evaluation of response compared to MRI

A

18F-FDG PET/CT should be coupled with sensitive bone marrow-based assays as part of MRD detection insideand outside the bone marrow

B

Cavo M. et al, Lancet Oncology 2017

Actions to achieve, maintain MRD negativity and

improve the prognosis• Integrate all active treatment tools up-front through:

• Sequential blocks of therapy

• Combination regimens

• Inclusion of new novel-agents:

• Second generation PI

• Monoclonal Ab

• Most effective treatments at relapse

• To treat the disease early on:

• In most malignancies early detection and intervention is a pre-requisite for

cure

• Design of more individualized approach :

• Risk-adapted treatment strategies

• MRD-adapted treatment strategies