Diagnostik beim Multiplen Myelom

Hartmut Goldschmidt

Sektion Multiples Myelom

Medizinische Klinik V, Universität Heidelberg

Nationales Centrum für Tumorerkrankungen Heidelberg

11. Oktober 2014

1. Anstellungsverhältnis oder Führungsposition

2. Beratungs- bzw. Gutachtertätigkeit

Onyx, Millenium, Janssen, Celgene

3. Besitz von Geschäftsanteilen, Aktien oder Fonds

4. Patent, Urheberrecht, Verkaufslizenz

5. Honorare

Janssen-Cilag, Celgene, Novartis

6. Finanzierung wissenschaftlicher Untersuchungen

Janssen-Cilag, Polyphor, Celgene, Novartis, Chugai, Janssen, Celgene,

7. Andere finanzielle Beziehungen

8. Immaterielle Interessenkonflikte

Introduction

Data from Kyle RA, et al. Mayo Clin Proc. 2003;78:21-33.

97%

66%

58%

19%

13%

11%

4%

4%

3%

73%

0 10 20 30 40 50 60 70 80 90 100

S/U M protein

Anaemia

Lytic bone lesions

Bone pain

Renal insufficiency

Hypercalcaemia

Minor or no abnormalities

Hepatomegaly

Amyloidosis

Non-secretory (no S/U M protein)

Patients (%)

Presenting features of MM

Diagnostic Criteria for Myeloma

Patient Criteria MGUS[1,2] Smoldering

Myeloma[1]

Symptomatic

Myeloma[1]

M-protein < 3 g/dL spike ≥ 3 g/dL spike

and/or

In serum and/or

urine[2]

Monoclonal

plasma cells in

bone marrow, %

< 10

≥ 10

≥ 10[2]

End-organ

damage

None None ≥ 1 CRAB*

feature[3]

1. IMWG. Br J Haematol. 2003;121:749-757. 2. Kyle RA, et al. N Engl J Med. 2002;346:564-569.

3. Durie BG, et al. Hematol J. 2003;4:379-398.

*C: Calcium elevation (> 10.5 mg/L or ULN)

R: Renal dysfunction (serum creatinine > 2 mg/dL)

A: Anemia (Hb < 10 g/dL or 2 g < normal)

B: Bone disease (lytic lesions or osteoporosis)

1950s

2008

Exposed surface

Hidden surface

Free Light Chain

p53

t 4;14

Del 13q

FISH Expression Profile & aCGH MRI

N MGUS MM

% r

ec

urr

en

ce

1 2 3 4 5 6 7 8 9 10 11 12 13 15 17 19 21 X Chr.

46 amplicons – 658 genes

Multiple Myeloma Diagnostic Advances

Professor Munshi, 2008

Diagnostic Tools: Basics

•History and physical examination

•Blood and urine – full blood count

– serum or plasma electrolytes, urea, creatinine, calcium, albumin, uric acid

– electrophoresis of serum and concentrated urine, immunofixation

– quantification of non-isotypic serum immunoglobulins

– quantification of serum paraprotein

– quantification of urinary light chains

– Free light chain test

– creatinine clearance, measured or calculated

– 2-microglobulin, C-related protein, LDH

– plasma viscosity

– (serum erythropoietin)

– (vitamin B12/folate)

•Skeletal survey – X-rays of spine, pelvis, skull, humeri, femora

– MRI for investigation for suspected spinal cord compression

– CT for extramedullary disease

•Bone marrow aspirate ± trephine biopsy – cytogenetics, FISH, immunophenotyping, (clonality studies)

Diagnosis and Investigation

Smith A, et al. Br J Haematol. 2005;132:410-51.

Kyle RA and Rajkumar SV. Cecil Textbook of Medicine, 22nd Edition, 2004

Kyle RA and Rajkumar SV. Cecil Textbook of Medicine, 22nd Edition, 2004

Monoclonal Protein in Myeloma

Immunofixation to Determine Type of Monoclonal Protein

IgG kappa

M protein

Kyle RA and Rajkumar SV. Cecil Textbook of Medicine, 22nd Edition, 2004

Serum Free Light Chains

• New tests can more

accurately measure

free serum light

chains (FLC)

• Correctly identified

224/224 patients

with light chain

disease

• 23/28 patients with

“non-secretory”

disease had

abnormal values

Adapted from http://www.bindingsite.co.uk/freelite.asp.

Bradwell, AR et al. Lancet 361:489-491, 2003.

Drayson, M et al. Blood 97:2900-2902, 2001. Katzmann et al Clin Chem 2002

0.1

1

10

100

1000

10000

100000

0.1 1 10 100 1000 10000 100000

Serum Kappa (mg/L)

Seru

m L

am

bd

a (

mg

/L)

Normal sera

Kappa LCMM

Lambda LCMM

Renal impairment

Smoldering Myeloma

Dispenzieri A et al., 2008, Blood I Larsen JT et al., 2013, Leukemia

kappa/lambda FLC-Ratio (<1/8 oder >8)

Involved light chain ≥100

Multiple Myeloma – Stringent CR and Prognosis

Kapoor et al., JCO, 2013

stringent complete Remission (sCR)

KM-Biopsie/IHC: no clonal Plasmacells

involved FLC in Serum normal, FLC-Ratio normal

Plasma Cell Morphology

Immunophaenotyping at Diagnosis

• EuroFlow panel

• 1309 Patienten: 486 MM 497 MGUS 114 SMM

Paiva et al, Leukemia 2013

Paiva et al, Leukemia 2013

Immunophaenotyping and Prognosis

• EuroFlow panel

• 1309 Patienten: 486 MM 497 MGUS 114 SMM

Salamanca-Data Paiva et al.

Symptomatic MM Smoldering MM MGUS

Smoldering Multiple Myeloma

Diagnostic Criteria for Myeloma

Patient Criteria MGUS[1,2] Smoldering

Myeloma[1]

Symptomatic

Myeloma[1]

M-protein < 3 g/dL spike ≥ 3 g/dL spike

and/or

In serum and/or

urine[2]

Monoclonal

plasma cells in

bone marrow, %

< 10

≥ 10

≥ 10[2]

End-organ

damage

None None ≥ 1 CRAB*

feature[3]

1. IMWG. Br J Haematol. 2003;121:749-757. 2. Kyle RA, et al. N Engl J Med. 2002;346:564-569.

3. Durie BG, et al. Hematol J. 2003;4:379-398.

*C: Calcium elevation (> 10.5 mg/L or ULN)

R: Renal dysfunction (serum creatinine > 2 mg/dL)

A: Anemia (Hb < 10 g/dL or 2 g < normal)

B: Bone disease (lytic lesions or osteoporosis)

Hillengass et al, JCO, 2010

Progression Risk Symptomatic MM

Time since MRI (months)

Smoldering Myeloma – MRI

0 1 2 3 4 5 6 7 8

Years since Bone Marrow Assessment

no del(17p)/t(4;14)/+1q21

del(17p)/t(4;14)/+1q21

p=0.0021

0

20

40

60

80

100 P

rob

ab

ility

of P

rogre

ssio

n (

%)

Line N Cytogenetics Median time (years)

147 (64.5%) standard-risk 5.62

81 (35.5%) high-risk 3.70

Smoldering Myeloma – Cytogenetics Progression Risk Symptomatic MM

Neben et al., JCO 2013

Algorithm for reclassifying SMM and

active MM

*Consider including pts with del17p, t(4;14), 1q21 gains as active MM

(could account for ~ 30% of SMM pts) §Consider using more than 1 FDG-avid lesion on PET/CT instead of MRI

Dispenzieri et al. Blood 2013; 122(26):4172-4181

High-risk Smoldering Myeloma =>

Consequences

• Results of the Spanish Myeloma Lenalidomid

study published by M.V. Mateos in the NEJM will

influence daily practice

• Other ongoing studies with Siltuximab,

Elotuzumb, anti BHQ, MLN9708…..

• Trials to cure SMM like Ola Landgren´s study at

NCI/NY are ongoing

• before further study results available: carefully

watch and wait

B. Durie, IMW 2013

M.V. Mateos et J. S. Miguel, NEJM 2013

Symptomatic Multiple Myeloma

Diagnostic Criteria for Myeloma

Patient Criteria MGUS[1,2] Smoldering

Myeloma[1]

Symptomatic

Myeloma[1]

M-protein < 3 g/dL spike ≥ 3 g/dL spike

and/or

In serum and/or

urine[2]

Monoclonal

plasma cells in

bone marrow, %

< 10

≥ 10

≥ 10[2]

End-organ

damage

None None ≥ 1 CRAB*

feature[3]

1. IMWG. Br J Haematol. 2003;121:749-757. 2. Kyle RA, et al. N Engl J Med. 2002;346:564-569.

3. Durie BG, et al. Hematol J. 2003;4:379-398.

*C: Calcium elevation (> 10.5 mg/L or ULN)

R: Renal dysfunction (serum creatinine > 2 mg/dL)

A: Anemia (Hb < 10 g/dL or 2 g < normal)

B: Bone disease (lytic lesions or osteoporosis)

International staging system for

symptomatic myeloma

Stage Criteria

Stage I ß2-M < 3.5 mg/L and

serum albumin ≥ 3.5 g/dL

Stage II Not stage I or III

Stage III ß2-M ≥ 5.5 mg/L

Greipp PR, et al. J Clin Oncol. 2005;23:3412-3420.

Stage I

Stage II

Stage III

Deaths, n/N

606/1111

1054/1505

968/1305

Median

in Mos

62 (58,65)

44 (42,45)

29 (26,32)

100

80

60

40

20

0

0 24 48 72 96 120 144 168 192 216

Mos From Initial Chemotherapy

Treatment

Pe

rce

nta

ge

Disease-specific factors

• Cytogenetics / FISH

• GEP

• Extramedullary disease

• ISS stage

• Renal failure due to MM

• Plasma cell leukemia

• LDH

• High proliferation rate /

labelling index

• Anemia

• Phenotype of tumor cell

Patient-specific

factors • Age

• Comorbidities, e.g. renal

failure, spinal cord

compression

• Socio-economic class /

occupation / lifestyle factors

/ family support

Avet-Loiseau, Hamburg, 2011

Avet-Loiseau, IMW 2013

Factors that determine high-risk disease

BM-aspirate

Ficoll

WBM Lysis

MNC

MACS

CD138+ MMC

Phenotypic characterization (MRD)

FACSAria

Plasma cell content [%]

mRNA DNA cells miRNA DNA

iFISH GEP Sequencing aCGH miRNome

Molecular Profiling – Strategy Heidelberg

Years since first HDT

OS

Pro

ba

bil

ity

0 1 2 3 4 5 6 7 8 9 10 11 12

0.0

0.2

0.4

0.6

0.8

1.0

Years since first HDT

PF

S P

rob

ab

ilit

y

0 1 2 3 4 5 6 7 8

0.0

0

.2

0.4

0

.6

0.8

1

.0

Overall Survival Progression-free Survival

Favorable

Intermediate

Poor Poor

Intermediate

Favorable

Favorable: NONE of the following aberrations del 13q, del 17p, +1q21, t(4;14), t(14;16)

Intermediate: del 13q and / or +1q21

Poor: del 17p and / or t(4;14), and / or t(14;16) Neben et al. Haematologica 2012

FISH based risk score (Translocations t(4;14) and t(14;16), deletions 13q14 and 17p13, gain 1q21

Comparison between both study arms HD4

Deletion 17p13

Months since randomisation

12 24 36 48 600

Pro

gre

ssio

n-f

ree

su

rviv

al

(%)

60

0

20

40

80

100

Months since randomisation

12 24 36 48 600

Overa

ll s

urv

ival

(%)

60

0

20

40

80

100

Comparison between both study arms

Deletion 17p13

PFSPFS OSOS

del (17p), arm A (without Bortezomib)

no del (17p), arm A (without Bortezomib)

del (17p), arm B (with Bortezomib)

no del (17p), arm B (with Bortezomib)

K. Neben et al., Blood 2012

Hose et al., Haematologica 2011

Gene expression-based proliferation index (GPI)

Event-free survival

P=.002

GPIhigh

GPImedium

GPIlow

GPIhigh

GPImedium

GPIlow P=.002

Overall survival

Genexpression and prognosis

Why ? Lots of prognostic factors…

Example: Patient *1968

• UAMS score (Shaugnessy et al.): high risk

• IFM score (Decaux et al.): low risk

• GPI (Hose et al.): medium risk

• ISS stage: 1

• Translocation t(4;14): yes ?

Prognosis in MM - metascoring

P<0.001

low risk

medium risk

high risk

P<0.001

low risk

medium risk

high risk

19 %

61 %

89 %

Event-free survival Overall survival

Meißner et al., Clin Cancer Res 2011

Prognosis in MM - metascoring

Bone Destruction in Multiple Myeloma

Whole Body CT

comparison of whole body CT with radiological skeletal survey

Functional Information

Imaging Techniques in MM

• X-ray

• Computed Tomography (CT)

• Magnetic Resonance Imaging (MRI)

• Positron Emission Tomography w/o CT

(PET/CT)

Bone

Jens Hillengass University of Heidelberg

Bone Marrow

Bäuerle T et al. Radiology 2009

Comparison of spinal MRI and whole body MRI

axial extra-axial

Localization of focal lesions

Bäuerle T, Hillengass J et al. Radiology 2009

Comparison of spinal MRI and whole body MRI

0 1-10 11-20 > 20

0

10

20

30

40

50

60

1. MRI

2. MRI

Number of focal lesions

Num

be

r o

f p

atien

ts

Hillengass et al., Haematolgica 2012

Whole body - MRI in MM (n=100): Comparison: start of therapy – after ASCT

Genetics, SNIPs and ………

„Germline genetics of multiple myeloma: explaining

disease risks and cytogenetic and gene expression

patterns.“ (Krebshilfe)

Genetic

Variation

Cytogenetics

Expression

Prognosis

?

? ?

Germline Tumor

?

?

Common variation at 3q26.2, 6p21.33, 17p11.2

and 22q13.1 influences multiple myeloma risk

Daniel Chubb, Niels Weinhol………..

Cytogenetic subgroups

The CCND1 c.870G>A polymorphism is a risk

factor for t(11;14)(q13;q32) multiple myeloma

Niels Weinhold,....... Kari Hemminki**

Andrulis et al., Cancer Discovery 2013

Clinical Inhibition of BRAF V600E

• First strictly biomarker- driven

GMMG trial

• Relapsed/refractory MM

• Confirmed BRAF V600

• Combined BRAF/MEK inhibition

• Centralized pre-screening

(Pathology, HD; n=500)

• Patient identification:

74 GMMG sites

• Treatment: 5 GMMG centers

GMMG Phase II Trial: LGX818+MEK162 in Multiple

Myeloma with activating BRAF mutations

mod. nach M.-S.Raab

Thank you for your attention!