Post on 03-Jan-2016
transcript
Myeloma Basics
Rodger Tiedemann
M.D., Ph.D., F.R.A.C.P., F.R.C.P.A.
Assist. Professor of Medicine, University of TorontoSenior Scientist & Staff Physician, Ontario Cancer Institute
Princess Margaret Hospital
Overview
Pre-Bcell
NaiveB cell
Interfollicular area
Immature B-cell
ProgenitorB-cell
What are plasma cells?
Follicular area
FDC
Lymph Node
Germinal CentreB-cell development
Ag
Pre-Bcell
NaiveB cell
Follicular B blast
Centroblast
Centrocyte
MarginalZone
MemoryB-cells
Plasma cell
ExtrafollicularB-Immunoblast
Interfollicular area
Immature B-cell
ProgenitorB-cell
What are plasma cells?
Follicular area
FDC
Ag
Lymph Node
Germinal Centre
SHM+
class switching
Germs
IgM IgG IgA
B-cell affinity maturation
What are antibodies?
light chain – κ, λ
heavy chain – G, A, M, E, D
What is an M-protein? SPEP
Polyclonal smear
M-spike
Normal antibody repertoire
Myeloma antibodies
Understanding your Bloodwork
• Donna Reece9:30-10:15
Stepwise progressionStepwise progression
MGUSSmoldering
MMActiveMM
Extramedullary
Clonal cellsClonal cells
PC > 10%PC > 10%
End organ damageEnd organ damage
BM independentBM independent
InternationaI Working Group (IWG) diagnostic criteria
MMAn M-protein
(in serum or urine) +
Marrow plasmacytosis or soft tissue
plasmacytoma (clonal) +
End-organ damage: ‘CRAB’
SMM
Serum M-protein ≥3.0 g/dL
and / orMarrow plasma cells ≥10%
(clonal) +
No related organ or tissue impairment
MGUS
Serum M-protein <3.0 g/dL +
Marrow plasma cells <10% +
No related organ damage No other B cell NHL or
amyloidosis
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 Near tetradiploid >75
Pseudodiploid 44/45 – 46/47
Leif BergsagelLeif Bergsagel
Marta ChesiMarta Chesi
5+ recurrent chromosome translocations (breakages) in MM
15%
5%2%
15%
1%
55%
3%3%
1%
FGFR3/MMSET
c-MAF
MAF-B
MAF-A
CYCLIN D1
CYCLIN D2
CYCLIN D3
OTHER
HYPERDIPLOID
9 Types of Myeloma
IgH translocationHyperdiploid
Pre-Bcell
NaiveB cell
Mantlezone
Follicular B blast
Centroblast
Centrocyte
MarginalZone
MemoryB-cells
ExtrafollicularB-Immunoblast
Interfollicular area
Immature B-cell
ProgenitorB-cell
What causes Multiple Myeloma?
Follicular area
FDC
Ag
Lymph Node
Germinal Centre
SHM+
class switching
IgM IgG IgA
MGUSMultipleMyeloma
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
What sparks the first mutation(s) that lead to MM?
??????“break”
Erroneous DNA repair?
attempted repair“break”
insult
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
R. Fonseca et al. Blood 2003
Chromosomal abnormalities (by FISH)
t(4;14)
t(14;16)13
-17p13.1
Shaughnessy, J. D. et al. Blood 2007;109:2276-2284
Gene expression-defined high-risk signature
What medicines are available?
Alkylating agents
Dr “Danny” BergsagelDr “Danny” Bergsagel
melphalanmelphalan cyclophosphamidecyclophosphamide prednisoneprednisone dexamethasonedexamethasone
Glucocorticosteroids
19581958 19671967
Previous standard of care: circa 1999
< 70y< 70y(Vincristine) (Adriamycin)
Dexamethasone
(Vincristine) (Adriamycin)
Dexamethasone
> 70y> 70y ??
inductioninduction consolidationconsolidation maintenancemaintenance
Repeat?Repeat?
MelphalanPrednisoneMelphalanPrednisone
Melphalan 200mg/m2
with autologous SCTMelphalan 200mg/m2
with autologous SCT?steroid
?interferon?steroid
?interferon
IMiDs: Thalidomide, Lenalidomide and Pomalidomide
Lenalidomide15-25 mg/d
MyelosuppressionSkin rash
DVT
NNHO O
O
NH2
Structurally similar, but functionally different, both qualitatively and quantitatively
N
N
O
O
O
O
Thalidomide100-200 mg/d
NeuropathyConstipation
SedationDVT
Pomalidomide 1-4 mg/d
N
O
O
NH
O
O
N H 2
MOA of IMiDS
Teo SK, AAPS Journal. 2005; 07(01): Teo SK, AAPS Journal. 2005; 07(01):
NH
ONH
O
OO
H
H
HN
NH
OHN
O
O
NH
O
N
O O
O
Carfilzomib
Irreversible
Proteasome (Thr)
NH
HN B
O
OH
OH
O
N
N CH
CH
O
HN
R
O
HN B
HOOH
Bortezomib
Slowly reversible
(Thr or Ser protease)
Proteasome Inhibitors
Proteasome inhibition
Xproteasome
Myeloma cell
trash
Proteasome inhibited(e.g. with Velcade)
Trash++
How can these drugsbe best used?
Many patients do well with Revlimid induction & transplantE4A03: Overall Survival after 4x Rev/Dex + Auto SCT
P=NS
Su
rviv
al P
rob
ab
ility
0
20
40
60
80
100
Time in Months
0 6 12 18 24 30 36
50 50 49 48 47 35 20
40 40 40 38 37 32 21
Numbers at RiskRD
Rd
Rd
RD 92%
3-year OS rate
HDM+Transplant following 4 cycles of RD vs. Rd
Transplant N = 90
(median age: 57 years)
Median F/U: 36 months
Rajkumar et al, 2008.
Lenalidomide (Revlimid) does not overcome classical high-risk
0
.2
.4
.6
.8
1
PFS
0 10 20 30 40 50
time (months)
Standard Risk
High Risk P < 0.001median 18.5 months
median 36.5 months
Rev/DexRev/Dex
Bortezomib improves outcome (OS) in high-risk MM, including t(4;14).
Low risk MM, no t(4;14) or -17pLow risk MM, no t(4;14) or -17p High risk MM, t(4;14)High risk MM, t(4;14)
Bortezomib added to TT3 but absent from TT2Bortezomib added to TT3 but absent from TT2
Pineda-Roman et al., Br J Haematol. 2008 Mar;140(6):625-34 Pineda-Roman et al., Br J Haematol. 2008 Mar;140(6):625-34
OS
TT3TT3 TT2TT2TT2 + ThalTT2 + Thal
TT3TT3
TT2TT2
TT2 + ThalTT2 + Thal
MM response rates: new drugs and combinationsMM response rates: new drugs and combinations
% of patientsresponding
Old regimens New regimens
Current Approaches for the Newly Diagnosed Patient
• Dr Keith Stewart1:00-1:45
• Dr Donna Reece1:00-1:45
What to do at Relapse