Van MGUS tot MULTIPEL MYELOOM
Ontmoetingsdag Interne Geneeskunde
Dr. Karel Fostier
Prof. Dr. Rik Schots
MGUS/MM Ontmoetingsdag IG 25-4-2014
MYELOOMKLINIEK
UZ Brussel
Monoclonal gammopathy undetermined significance
MGUS (0.8 g/dL)
Polyclonal increase
gammaglobulins (2.32 g/dL)
Extra fraction?
MGUS/MM Ontmoetingsdag IG 25-4-2014
MGUS 0.6 g/dL
Small extra fraction?
Neuropathy
Myeloma (IgG)
MGUS/MM Ontmoetingsdag IG 25-4-2014
Myeloma (IgA)
MGUS/MM Ontmoetingsdag IG 25-4-2014
Paraproteins
Intact monoclonal
immunoglobulin
Serum protein electrophoresis
M-component = M-spike
= monoclonal gammopathy
Monoclonal plasma cells
or mature B lymphocytes
If > renal treshold
Excess free light chain
(kappa or lambda)
MGUS/MM Ontmoetingsdag IG 25-4-2014
Bence Jones protein
in urine (not detected
by dipsticks!)
MDisorders associated with a paraprotein
a
t
u Plasma cell disorders
 Click to edit the
r

Monoclonal gammopathy of
outline text format
e undetermined significance (MGUS)
B
 Second Outline
c  Multiple myeloma

Symptomatic myeloma
e
Level

Asymptomatic or smoldering myeloma
l

Solitary plasmocytoma
l
 Third Outline

POEMS syndrome
t

LA amyloidosis
Level
u  Cryoglobulinemia
m  Heavy chain disease
 Fourth
o
Outline Level
r
s
 Fifth
N
o
n
MGUS/MM
Ontmoetingsdag IG 25-4-2014
H
Outline
Level
 Sixth
MGUS: diagnostic criteria
All required:
1. M-protein in serum < 3 g/dL
2. Bone marrow clonal plasma cells < 10% and low level of
plasma cell infiltration in a trephine (if done)
3. No myeloma-related organ or tissue impairment (including
bone lesions) or symptoms
4. No evidence of other B-cell proliferative disorders or light-chain
associated amyloidosis or other light chain, heavy-chain or
immunoglobulin-associated tissue damage
Smith et al. BJH 2005, (The International Myeloma Working Group guidelines)
MGUS/MM Ontmoetingsdag IG 25-4-2014
Prevalence of MGUS
Age group (yrs)
Men
Women
Total
50 – 59
2%
1.4%
1.7%
60 – 69
3.7%
2.3%
3.0%
70 – 79
5.6%
3.8%
4.6%
≥ 80
8.3%
6.0%
6.6%
Total
3.7%
2.9%
3.2%
Kyle et al. NEJM 2006
MGUS/MM
Ontmoetingsdag IG 25-4-2014
MGUS
MGUS: rate of progression?
%?
MGUS
Genetic background
Environmental factors
Immune dysregulation
normal
plasma cells
MGUS/MM Ontmoetingsdag IG 25-4-2014
MM
Prognosis in MGUS
Probability of progression to
 Symptomatic myeloma (RR=25)
 IgM lymphoma (RR=2.4)
 Primary amyloidosis (RR=8.4)
 Waldenström (RR=46)
 CLL (RR=0.9)
 Plasmacytoma (RR=8.5)
MGUS: risk of developing symptomatic myeloma is 1% per year
Kyle et al. NEJM 2002; Bladé NEJM 2006
MGUS/MM Ontmoetingsdag IG 25-4-2014
MGUS  MM: genetic events
Event
MGUS
Ig translocations
SMM
50%
MYC dysregulation
Del 13
Gain 1q21
MM
55-70%
0%
PCL
HMCL
85%
>90%
44%
40-50%
0%
Rel/refr
MM
90%
50%
45%
43%
Loss 17p
rare
10%
Ras mutations
rare
10%
NFKB activation
20%
Stroma dependent
MGUS/MM Ontmoetingsdag IG 25-4-2014
72%
40%
35-50%
35-50%
45%
Stroma independent
MGUS  Myeloma
MGUS/MM Ontmoetingsdag IG 25-4-2014
MGUS probability of progression
Proportion of
patients
Absolute risk of
progression at
20 yrs
Taken into
account the risk
of other causes
of death
39%
5%
2%
Low-intermediate
(1 factor)
36.5%
21%
10%
High-intermediate
(2 factors)
20%
37%
18%
High-risk
(3 factors)
4.5%
58%
27%
Low-risk
(0 factors)
Risk factors = serum M-protein ≥ 1.5 g/dL; non-IgG subtype;
abnormal FLC ratio
MGUS/MM Ontmoetingsdag IG 25-4-2014
Detecion M-spike in the serum: algorithm
MGUS/MM Ontmoetingsdag IG 25-4-2014
Distinct entities associated with MGUS

Osteopenia and bone fractures



Thrombosis




Risk of vertebral (x6) and hip fractures (x1.6) is increased
Independent of risk of progression
x3.4, x2.1, x2.1 for VTE at 1, 5, 10 years
x1.7, x1.3, x1.3 for arterial thrombosis at 1, 5, 10 years
Effect on platelet aggregation?
Peripheral neuropathy


PNP of unknown cause  M-component in 10% of cases
IgM (60%), IgG (30%), IgA (10%)
MGUS/MM Ontmoetingsdag IG 25-4-2014
Caveats with monoclonal gammopathies

Small but dangerous peaks





IgA myeloma


LA amyloidosis
Cryoglobulinemia
Polyneuropathy
Associated lymphoproliferative diseases
Spike in the beta region
Non-secretory or light chain myeloma


No apparent M-spike on electrophoresis
Hypogammaglobulinemia
MGUS/MM Ontmoetingsdag IG 25-4-2014
Typical symptomatic myeloma
Monoclonal
plasma cells in the
bone marrow
Bone abnormalities
Renal impairment
MGUS/MM Ontmoetingsdag IG 25-4-2014
Monoclonal
gammopathy
Hypercalcemia
Immune deficiency
Multiple myeloma: epidemiology
MGUS/MM Ontmoetingsdag IG 25-4-2014
Myeloma: diagnostic criteria
Asymptomatic myeloma


M-protein in serum > 3g/dL
and/or BM clonal plasma cells >10%
No MM related organ or tissue
impairment or symptoms
Symptomatic myeloma



M-protein in serum and/or urine
BM clonal plasma cells or biopsy
proven plasmacytoma
Any MM-related organ or tissue
impairment (if uncertain: 30% BM
PC is required)
Myeloma-related organ or tissue impairment





[C] Increased serum calcium (> 10 mg/dL)
[R] Renal insufficiency attributable to myeloma
[A] Anemia: Hb < 10 g/dL (or 2 g/dL below normal limit)
[B] Bone lesions: lytic lesions or compression fractures
Other: symptomatic hyperviscosity, amyloidosis, recurrent bacterial
infections (ie > 2 episodes per year)
Smith et al. BJH 2005; 132: 410-451 (The International Myeloma Working Group guidelines)
MGUS/MM Ontmoetingsdag IG 25-4-2014
Myeloma: bone lesions
MGUS/MM Ontmoetingsdag IG 25-4-2014
Myeloma: bone lesions
MGUS/MM Ontmoetingsdag IG 25-4-2014
Myeloma: bone lesions
MGUS/MM Ontmoetingsdag IG 25-4-2014
Myeloma: bone lesions
MGUS/MM Ontmoetingsdag IG 25-4-2014
ISS staging system
MGUS/MM Ontmoetingsdag IG 25-4-2014
Greipp et al. JCO 2005
Risk score
520 pts
Median follow-up 90 mths
No novel agents
Risk factors:

Age > 55 yrs

Beta-2 mcg > 5.5 mg/L

t (4;14)

del 17p

+ 1q
% with risk
0
1
2
3
factors and median OS (yrs)
20%

> 10
44%

9.5
25%

5.8
11%

2.8
MGUS/MM Ontmoetingsdag IG 25-4-2014
Avet-Loiseau et al. JCO 2012
Rol van het microenvironment
Proteasoom inhibitie
IMiDs
MGUS/MM Ontmoetingsdag IG 25-4-2014
Myeloom behandeling (verleden)
Oraal melfalan
prednisone
Complexere chemotherapeutische
schema’s (VAD/VMCP-VBAP)
Autologe beenmergtransplantatie (experimenteel)
1962
1983
1984
1986
Hoge dosis melfalan
Hoge dosis dexamethasone
MGUS/MM Ontmoetingsdag IG 25-4-2014
Overleving myeloompatiënten 1980 - 1995
30% 4 jaars-overleving
MGUS/MM Ontmoetingsdag IG 25-4-2014
Boccadoro et al. JCO 1991
Myeloom behandeling (heden)
Hoge-dosis melfalan
+
Stamcelransplantatie
1996
Proteasoom
Inhibitor
Bortezomib (Velcade®)
1999
Thalidomide
2003
Lenalidomide (Revlimid®)
Immunomodulatoire
Geneesmiddelen (IMiDs®)
MGUS/MM Ontmoetingsdag IG 25-4-2014
2005
Prognose multipel myeloom
Click to edit the
Nieuwe combinaties
Hoge dosis chemotherapie outline
text format
Geïndividualiseerde

+
Autologe
stamceltransplantatie
5-jaars
overleving
50%
behandeling
 Second
Outline
Nieuwe geneesmiddelen
Level

Third Outline
Level
 Fourth
30%
Chemotherapie
10%
1975
1995
MGUS/MM Ontmoetingsdag IG 25-4-2014
Outline Level
Thalidomide
Velcade®  Fifth
Revlimid®
Outline
2000
2014
Level
 Sixth
Standard of care
AGE
Transplant-eligible (<65 yrs)
Induction (3-4 mnths)
(Velcade-based)
Stem cell mobilization
Autologous stem cell
transplantation
after high-dose melphalan
Consolidation/Maintenance
MGUS/MM Ontmoetingsdag IG 25-4-2014
Not transplant-eligible (>65 yrs)
Melphalan+Prednisone+Velcade
(MPV)
Eerstelijnsbehandeling (patiënt < 65 jaar)
Inductietherapie = ambulante setting
4 cycli van 3 weken
Velcade 1.0 mg/m² SC (d1, 4, 8, 11)
Thalidomide 100 mg /d PO
Dexamethasone 40 mg / 20 mg PO (d1,2,4,5,8,9,11,12)
vTD
CR
(4 cycli)
CR/VGPR
na ASCT
Stamcelaferese
(GCS-F 10 µg/kg/dag)
31%
74%
Melfalan 200 mg/m²
+ ASCT
(3 weken hospitalisatie)
(Consolidatiebehandeling)
(Onderhoudsbehandeling)
MGUS/MM Ontmoetingsdag IG 25-4-2014
Moreau et al. Blood 2011
Overleving na autologe stamceltransplantatie
Frontline regimen
ASCT
Consolidation/maintenance
80% 4-jaars overleving
MGUS/MM Ontmoetingsdag IG 25-4-2014
Spencer et al. JCO 2009
Genezing mogelijk?
Genezing?
MGUS/MM Ontmoetingsdag IG 25-4-2014
Mateos et al. Blood 2011
Eerstelijns behandeling (patiënt > 65 jaar)
VMP-schema
 Click
to
Bortezomib (Velcade®) 1,3 mg/m²
SC bolus
edit the
outline
Melfalan 9 mg/m² PO + Prednisone
60 mg/m²text
PO format

Cyclus 1-4
1
4
Cyclus 5-9
8
11
22
25
Second Outline
Level

Third
Outline
32
Level
29
 Fourth
1
8
22
MGUS/MM Ontmoetingsdag IG 25-4-2014
29
x3
42
x6
Outline Level42
 Fifth
Outline
Level
 Sixth
San Miguel et al. NEJM 2008
Overleving na VMP
50% 5-jaars overleving
MGUS/MM Ontmoetingsdag IG 25-4-2014
Mateos et al. JCO 2010
Complicaties van ziekte en/of behandeling

Infecties





Anemie
Hypercalcemie
Nierinsufficiëntie






Bacterieel
Viraal (H Zoster)
Cast nefropathie
“Pathologische” botfracturen
Inzakkingsfractuur met parese/paralyse
Trombose
Neuropathie
Pijn


Botletsels
Neuropathische pijn
MGUS/MM Ontmoetingsdag IG 25-4-2014
Supportive care
IVIG
EPO
Bisfosfonaten
Tromboprofylaxis
Radiotherapie
Antibiotica/antivirale medicatie
MGUS/MM Ontmoetingsdag IG 25-4-2014
Kyfoplastie
Recidief – standaard schema’s
Regimen
Cyclophosphamide + thalidomide
+ dexamethasone (CTD)
Response rate
Response duration
(median)
55-60%
(10-15% CR)
10-12 mths TTP
Bortezomib
30%
(4% CR)
6 mths PFS
Bortezomib+dexamethasone
47%
(5% CR)
6 mths PFS
Bortezomib + cyclophosphamide
+ dexamethasone
75%
(31% CR)
7 mths PFS
Bortezomib+pegylated liposomal
doxorubicin
52%
(4% CR)
9.3 mths TTP
Lenalidomide+ dexamethasone
60%
(15% CR)
11 mths TTP
MGUS/MM Ontmoetingsdag IG 25-4-2014
Myeloom behandeling (toekomst)
Proteasoom inhibitie
Immunotherapie
Dendritische cel
vaccinatie*
Oprozomib
ONX 0912
Carfilzomib*
(Kyprolis®)
Ixazomib*
(MLN9708)
2012
2013
Lenalidomide
onderhoudstherapie
(anti- CS1) Elotuzumab*
(anti CD38) Daratumumab
2014 en verder
…
Plitidepsin*
Pomalidomide*
(Pomalyst ®)
HDACi*
Celcyclus arrest
Immunomodulatoire geneesmiddelen (IMiDs®)
MGUS/MM Ontmoetingsdag IG 25-4-2014
Epigenetische modificatie
* Klinische studies
Recidief– klinische studies

MLN9708


Carfilzomib


3de generatie immunomodulator
Elotuzumab


IV proteasoom inhibitor
Pomalidomide


PO proteasoom inhibitor
Anti-CS1 monoclonaal antilichaam
Plitidepsine

Inducer cel cyclus arrest
MGUS/MM Ontmoetingsdag IG 25-4-2014
Overleving myeloom patiënten UZ Brussel
Diagnose 01/01/2007-01/01/2014
leeftijd bij diagnose <65 jaar
65 jaar < leeftijd bij diagnose < 75 j
leeftijd bij diagnose > 75 j
Mediaan niet bereikt
Mediaan : 54 maanden
95% CI (39,7 - 68,3)
Mediaan : 29
maanden
95 % CI (12,1 –
45,9)
Cumulatieve 5-jaars overleving



MGUS/MM Ontmoetingsdag IG 25-4-2014
< 65 j
: 70 % ± 9%
65-75 j
: 54 % ± 10 %
> 75 % : 33 % ± 12 %
Dendritische cel therapie (MYVAC2)
WBC
selectie
+ GM-CSF
+ IL-4
monocyten
aferese
dendritische cellen
Myeloom
patient in
minstens
VGPR na ASCT
Elektroporatie
met mRNA
myeloomtargets en
maturatie stimuli
4-voudige DC vaccinatie
&
Lenalidomide
onderhoudstherapie
Ex-vivo
DCs activeren
anti-myeloom T-cellen
MGUS/MM Ontmoetingsdag IG 25-4-2014
TriMIX DC®
T cellen elimineren
residuele myeloomcel
MGUS/MM Ontmoetingsdag IG 25-4-2014
MGUS/MM Ontmoetingsdag IG 25-4-2014