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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!