PROGNOSTIC FACTORS
FOR MULTIPLE
MULTIPLE MYELOMA
MYELOMA
IN THE ERA OF NOVEL
THERAPIES
Joan Bladé, Laura Rosiñol, M. Teresa Cibeira
XIth International Myeloma
Myeloma Workshop
Workshop
Kos, June 27, 2007
Am J Med, 42: 937-948, June 1967
Prognostic Factors
Factors in
in MM
MM
Prognostic value...
A new prognostic factor...
A simple reliable marker...
An easily available p
yparameter...
An independent prognostic factor...
A new staging system...
Proposal for a novel p
pprognostic index...
Prognostic Factors
Factors in
in MM
MM
Clii
Clinical
d
an lb
lab
t
ora ory f t
ea ures
Staging systems
Malignant clone: molecular g
ggenetic status
Response to therapy
Mechanisms of disease control/progression
Prognostic Factors in MM
Clinical and Laboratory Features
Ht
Host characteristitics
Age
PS
Tumor burden
2-microglobulin
Organ damag
gge
Renal function
Hb
Main Staging Systems
Systems in
in MM
MM
Author, year
Parameters
Other
Durie and Salmon, 1975 Hb, Ca, M-protein, bone lesions Renal function
%PC, Cr, and Ca (IgG)
Merlini et
et al
al, 1980
Hb, Ca, M-protein (IgA)
MRC, 1980
Hb, urea, PS
Cavo et al, 1989
D & S, p
,platelet count
Greipp et al, 1988
2-microglobulin, LI
Bladé et al, 1989
Albumin, urea
San Miguel et al, 1989
Hb, Cr, PS, PI
S-phase, 2-microglobulin, age,
San Miguel et al, 1995
PS
IMWG, 2005
2-microglobulin, albumin
MRC: Medical Research Council; IMWG: International Myeloma Working Group; Hb: haemoglobin; Ca: calcium; PC: plasma
cells; Cr: creatinine; Ig: Immunoglobulin; PS: performance status; LI: labelling index; PI: paraprotein index.
International Prognostic
Prognostic System
System (IPS)
Stage
Overall Survival
(months)
I
-2M < 3.5 mg/L and albumin 3.5 g/dL
62
II
-2M < 3.5 mg/L
mg/L and albumin < 3 5
. g/dL
g/dL
44
or
-2-m 3.5 5.5 mg/L
III
-2M > 5.5 mg/L
29
Greipp P et al. J Clin Oncol 2005; 23: 3412-20.
Cytogenetic Prognostic Subgroups in
Ml
Mu ti
ltiple Myeloma
Good/average prognosis
Hyperdiploidy
t(11;14)(q32;q32): cyclin D1 upregulation
Bad prognosis
pg
Hypodiploidy
t(4;14)(p16.3;q32): FGFR3&MMSET upregulation
t(14;16)(q32;q23): c-MAF upregulation
Chromosome 1 abnormalities: 1q gains
(overexpression
(p
CKS1B)
17q deletions, 13q deletions
13q Deletion as
as Single
Single Abnormality
Abnormality
No independent prognostic impact
impact*
* Gutiérrez N et al. Leukemia 2007; 21: 541-9.
* Avet
Avet Loiseau
-
H et
et al
al. Blood
Blood 2007; 109: 3489-95.
Molecular Myeloma Subgroups
Gene Expression Profiling
"Translocation/Cyclin D" classification*:
5 groups
Recurrent translocations/hyperdiploidy**:
7 entities
* Bergsagel PL et al. Blood 2005; 106: 296-303.
** Zhan F et al. Blood 2006; 108: 2020-8.
High-resolution Genomic Profiles*
(aCGH/mRNA microarray/FISH/novel bioinformatics)
4 different MM subtypes
(recurrent DNA copy number changes), i.e.:
Hyperdiploid, 11q gains: good outcome
Hyperdiploid, 1q gains and/or 13 losses: poor
outcome
* Carrasco R et al. Cancer Cell 2006; 4: 313-25.
Response to Therapy as
Pt
Prognos i
tic Factor
Stabilization of disease
Impact of CR
With
i
pr mary th
therapy
After HDT/SCT
Therapy Against Cancer
"Myeloma" Stem Cell
ll
Plasma cell killing
lowest possible tumor mass
Meaning of CR achieved with novel therapies
Different effect of old and new drugs on the
bulk of differentiated plasma cells versus
the myeloma stem cell?
Novel Drugs
andN
d New Molecular Targets
Novel
drugs
can
overcome
drug
resistance in poor cytogenetic subgroups
New thi
herapies shl
hou d
ld target
ifi
spec c
molecular pathways
Monoclonal Gammopathies
MM
"EVOLV
EVOL IG
V
"
IG
SMM
"NON EVOLVING"
SMM
NON EVOLVING
"NON EVOLVING"
MGUS
Rosiñol et al. Br J Haematol 2003; 123: 631-36.
Rosiñol et al. Mayo Clin Proc 2007; 82: 428-34.
Possible Impact of Influencing on
Mh
Mechanisms of Di
Disease Progression
Evolving MGUS early/slowly evolving
myeloma
(escap
(ping
growth-restrainin
g
g
mechanisms)
Avoid disease progression after decreasing
tumor mass MGUS state (growth-
restraining influences)
When Is a "Prognostic Factor"
Really Prognostic?
Prognostic Classification for MM
1P
15 Predi
dictor Genes
Low risk (50% pts): OS 3 y = 95%
Intermediate risk (25% pts): OS 3 y = 81%
High risk (25% pts): OS 3 y = 47%