Transcript Myeloma Basics

Myeloma Basics
Rodger Tiedemann
M.D., Ph.D., F.R.A.C.P., F.R.C.P.A.
Assist. Professor of Medicine, University of Toronto
Senior Scientist & Staff Physician, Ontario Cancer Institute
Princess Margaret Hospital
Overview
What are plasma cells?
Lymph Node
Interfollicular area
Progenitor
B-cell
Pre-B
cell
Follicular area
Naive
B cell
Immature
B-cell
FDC
B-cell development
Germinal Centre
What are plasma cells?
Germs
Lymph Node
Interfollicular area
Ag
Progenitor
B-cell
Extrafollicular
B-Immunoblast
IgM IgG IgA
Pre-B
cell
Follicular area
Naive
B cell
Follicular B blast
Immature
B-cell
Centrocyte
Ag
FDC
SHM
+
class
switching
Centroblast
Germinal Centre
B-cell affinity maturation
Marginal
Zone
Memory
B-cells
Plasma
cell
What are antibodies?
light chain – κ, λ
heavy chain – G, A, M, E, D
What is an M-protein?
SPEP
Normal antibody repertoire
Polyclonal
smear
M-spike
Myeloma antibodies
Understanding your Bloodwork
• Donna Reece
9:30-10:15
Stepwise progression
MGUS
Smoldering
MM
Active
MM
Extra
medullary
Clonal cells
PC > 10%
End organ damage
BM independent
InternationaI Working Group (IWG) diagnostic criteria
MGUS
Serum M-protein <3.0 g/dL
+
Marrow plasma cells <10%
+
No related organ damage
No other B cell NHL or
amyloidosis
SMM
MM
Serum M-protein ≥3.0 g/dL
and / or
Marrow plasma cells ≥10%
(clonal)
+
No related organ or tissue
impairment
An M-protein
(in serum or urine)
+
Marrow plasmacytosis
or soft tissue
plasmacytoma (clonal)
+
End-organ damage:
‘CRAB’
MGUS
=Monoclonal gammopathy of undetermined significance
• prevalence increases with age:
• 3.2% at >50yo
• 5.3% at >70yo
• 7.5% at >85yo
• on average, 1% risk per year of progression to Multiple
Myeloma or lymphoma (7x risk ‘normal’ population)
• virtually all MM patients probably had MGUS before MM
MM Features
•
•
•
•
Calcium elevation
Renal disease
Anemia
Bone disease
•
M-protein
(often >30g/l in serum)
IgG > IgA > IgD or Light chain only
•
Clonal plasma cells
(often >10% in BM)
Smith. Br J Haematol. 2005;132:410.
What causes plasma cells
to become malignant?
Chromosomal changes in MM
Hypodiploid < 45
Hyperdiploid >46/47
Pseudodiploid 44/45 – 46/47
Near tetradiploid >75
5+ recurrent chromosome translocations (breakages) in MM
Leif Bergsagel
Marta Chesi
9 Types of Myeloma
Hyperdiploid
IgH translocation
FGFR 3/MMSET
15%
c-MAF
5%
2%
MAF-B
1%
MAF-A
CYCLIN D1
CYCLIN D2
55%
15%
CYCLIN D3
OTHER
1%
3%
3%
HYPERDIPLOID
What causes Multiple Myeloma?
Lymph Node
Interfollicular area
Progenitor
B-cell
Extrafollicular
B-Immunoblast
IgM IgG IgA
Pre-B
cell
Follicular area
Naive
B cell
Follicular B blast
Immature
B-cell
Centrocyte
Mantle
zone
Ag
FDC
SHM
+
class
switching
Centroblast
Germinal Centre
Marginal
Zone
Memory
B-cells
MGUS
Multiple
Myeloma
What sparks the first mutation(s) that lead to MM?
Increased risk of MM in individuals exposed to:
•
•
•
•
•
A-bomb
Radiation (e.g. radiologists & nuclear power plant workers
Pesticides? (evidence not compelling)
Benzene? (evidence not compelling)
Risk modified by gender & race
“break”
???
Erroneous DNA repair?
insult
“break”
attempted repair
Prognosis in MM?
International Staging System (ISS)
1
Serum ß2 microglobulin <3.5 mg/dL
+
Serum albumin ≥ 3.5 g/dL
2
Not 1 or 3*
3
Serum ß2 microglobulin >5.5 mg/dL
International Staging System vs OS
Chromosomal abnormalities (by FISH)
D13
t(14;16)
t(4;14)
-17p13.1
R. Fonseca et al. Blood 2003
Gene expression-defined high-risk signature
Shaughnessy, J. D. et al. Blood 2007;109:2276-2284
What medicines are available?
Alkylating agents
melphalan
1958
Dr “Danny” Bergsagel
cyclophosphamide
Glucocorticosteroids
prednisone
1967
dexamethason
e
Previous standard of care: circa 1999
induction
consolidation
maintenance
Repeat?
< 70y
(Vincristine)
(Adriamycin)
Dexamethasone
> 70y
Melphalan
Prednisone
Melphalan 200mg/m2
with autologous SCT
?steroid
?interferon
?
IMiDs: Thalidomide, Lenalidomide and Pomalidomide
O
O
O O
N
N
Thalidomide
100-200 mg/dO
Neuropathy
Constipation
Sedation
DVT
O
H
N
ON
NH2
Lenalidomide
15-25 mg/d
O
H
N
N
O
NH2
O
Pomalidomide
1-4 mg/d
Myelosuppression
Skin rash
DVT
Structurally similar, but functionally different, both qualitatively and quantitatively
O
MOA of IMiDS
Teo SK, AAPS Journal. 2005; 07(01):
Proteasome Inhibitors
Bortezomib
HO
O
HN
OH
H
N
N
B
OH
O
B
N
H
R
CH
OH
(Thr or Ser protease)
CH
O
HN
N
Slowly reversible
O
Carfilzomib
O
O
H
N
N
O
N
H
O
O
H
N
Irreversible
O
Proteasome (Thr)
N
H
O
Proteasome inhibition
Myeloma cell
Trash++
trash
X
proteasome
Proteasome inhibited
(e.g. with Velcade)
How can these drugs
be best used?
Many patients do well with Revlimid induction & transplant
E4A03: Overall Survival after 4x Rev/Dex + Auto SCT
HDM+Transplant following 4 cycles of RD vs. Rd
100
92%
RD
3-year OS rate
Rd
Survival Probability
80
60
40
Transplant N = 90
(median age: 57 years)
P=NS
20
Median F/U: 36 months
0
0
6
12
18
24
30
36
Time in Months
RD
Rd
50
40
50
40
49
40
Numbers at Risk
48
38
Rajkumar et al, 2008.
47
37
35
32
20
21
Lenalidomide (Revlimid) does not overcome classical high-risk
1
Rev/Dex
PFS
.8
.6
Standard Risk
median 36.5 months
.4
.2
High Risk
median 18.5 months
0
0
10
20
30
time (months)
40
P < 0.001
50
Bortezomib improves outcome (OS) in high-risk MM, including t(4;14).
Low risk MM, no t(4;14) or -17p
High risk MM, t(4;14)
OS
TT3 TT2
TT2 + Thal
TT3
TT2
TT2 + Thal
Bortezomib added to TT3 but absent from TT2
Pineda-Roman et al., Br J Haematol. 2008 Mar;140(6):625-34
MM response rates: new drugs and combinations
Old regimens
% of patients
responding
New regimens
Current Approaches for the Newly Diagnosed Patient
• Dr Keith Stewart
1:00-1:45
What to do at Relapse
• Dr Donna Reece
1:00-1:45