Clinical implications of t(11;14)(q13;q32),
t(4;14)(p16;q32) and -17p13 (p53) deletions in
myeloma patients treated with high dose
therapy
Morie A Gertz, MD 1, Martha Q Lacy, MD 1, Angela
Dispenzieri, MD 1, Philip R Greipp, MD 1, Mark R Litzow,
MD 1, Kim J Henderson, BA 1*, Scott A Van Wier, BA 2*,
Gregory J Ahmann, BA 2 and Rafael Fonseca, MD 2.
Hematology, Mayo Clinic, Rochester, MN 1, and
Scottsdale, AZ2
Molecular Cytogenetics in Myeloma
Introduction
· Nonrandom recurrent chromosomal
abnormalities are ubiquitous in multiple
myeloma
· IgH translocations in MM result in the up-
regulation of oncogenes and are seen in
50% of patients
· Important clinical implications are
suggested for these abnormalities
Molecular Cytogenetics in Myeloma
Background
· Prior work suggests t(11;14) have
improved survival while t(4;14) have
inferior TTP & OS following HDT
· ECOG conventionally treated patients
showed inferior outcomes with t(4;14)
· Deletion 13 is seen in half of
myeloma patients by FISH its
predictive value is less than when
seen with conventional cytogenetics
Keats: Blood 101,2003, Moreau: Blood 100,2002, Stewart: Br J Haematol 126, 2004
IMPACT OF FISH ON MYELOMA
Materials & Methods: Probes
· Standard cIg-FISH methodology
was used for detection of
·t(4;14)(p16.3;q32)
·t(11;14)(q13;q32)
·14q32 translocations (VH/CH)
·Chromosome 13 abnormalities
·Deletions of 17p13 (p53)
IMPACT OF FISH ON MYELOMA
Patients N=226
Characteristics of Transplanted Patients
Parameter
Range
Median
Male
142(60%)
Age (years)
30-71
56
Creatinine mg/dL
0.7 ­ 3.5
1.1
Beta 2-microglobulin mg/dL
0.9 ­ 11.2
2.53
Marrow Labeling Index, %
0 ­ 8.0
0.4
Marrow Plasma Cells, %
0 ­ 95
20
Serum M-protein, g/dL
0 ­ 10.4
1.6
Urine Protein, g/dL
0.007 ­ 10.4
0.09
Univariate Predictors of Outcome
Parameter
Overall Survival
Freedom from Progression
Log Rank P
Log Rank P Value
Value
Gender
.21
.56
Serum M Spike
.9
.82
Urine Total Protein
.1
.25
Beta 2 Microglobulin
.016
.14
LDH
.48
.6
C-Reactive Protein
.07
.64
Bone Disease
.11
.49
% Plasma Cells
.0002
.0001
Labeling Index
.0001
.0001
Creatinine
.42
.88
Age
.77
.77
13q
.004
.017
p53
.04
.003
11;14
.7
.35
4;14
.0001
.0001
Status at Stem Cell Transplant
.0001
.0001
TTP by t(4;14)(p16.3;q32)
1.0
0.9
0.8
0.7
4;14 absent N=127
Surviving
0.6
4;14 present N=26
0.5
Median 17.8 vs 8.2 P<0.0001
0.4
Progression
to 0.3
Time 0.2
Time
0.1
0.0
0
10 20
30 40 50 60
70 80 90 100 110 120 130
Response duration Months
Overall Survival by t(4;14)(p16.3;q32)
1.0
0.9
0.8
4;14 absent N=127
0.7
4;14 present N=26 (17%)
0.6
0.5
Median 38.3 vs 18.8 P<0.001
Surviving 0.4
0.3
0.2
0.1
0.0
0
10 20 30 40 50 60 70 80 90 100 110 120 130
survival from BMT
Post PSCT TTP by t(11;14)(q13;q32)
1.0
0.9
0.8
0.7
11;14 absent N=163
0.6
11;14 present N=34 (17%)
0.5
Progression
to Surviving 0.4
Median 20.1 vs 15.3 P=NS
0.3
Time
0.2
0.1
0.0
0
10 20 30 40 50 60 70 80 90 100 110 120 130
response duration
Post PSCT Survival by t(11;14)(q13;q32)
1.0
0.9
0.8
0.7
11;14 absent N=163
0.6
11;14 present N=34 (17%)
0.5
Median 34.8 vs 36.6 P=NS
Surviving 0.4
0.3
0.2
0.1
0.0
0
10 20 30 40 50 60 70 80 90 100 110 120 130
survival from BMT
Post SCT TTP by -17p13
1.0
0.9
0.8
0.7
p53 wild type N=150
0.6
p53 deleted N=18 (11%)
0.5
Median 16.1 vs 8.7 P=0.001
SurvivingProgression 0.4
to 0.3
Time 0.2
0.1
0.0
0
10 20 30 40 50 60 70 80 90 100 110 120 130
response duration
Post SCT Overall Survival by -17p13
1.0
0.9
0.8
p53 wild type N=150
0.7
p53 deleted N=18 (11%)
0.6
0.5
Median 38.8 vs 15.1 P=0.03
Surviving 0.4
0.3
0.2
0.1
0.0
0
10 20 30 40 50 60 70 80 90 100 110 120 130
survival from BMT
Impact of Biologic Correlates on TTP
Parameter
p
Hazard Confidence 95%
p53
.08
1.93
.92-3.7
t(4;14)
.0012
2.56
1.46-4.35
2-Micro
.53
1.03
.93-1.12
Label Index
.01
1.21
1.05-1.39
13
.051
1.50
.99-2.27
Relapse @
2.30
1.50-3.58
SCT
.0001
Impact of Biologic Correlates on Survival
(Cox)
Parameter
p
Hazard Confidence 95%
p53
.51
1.3
.54-2.75
t(4;14)
.006
2.16
1.26-3.62
2-Micro
.19
1.08
.96-1.20
Label Index .0001
1.34
1.17-1.52
13
.02
1.72
1.09-2.75
Relapse @
2.10
1.28-3.50
SCT
.003
Interaction of 13 & t(4;14)
· Deletion 13 by FISH found in 52% of
the entire cohort.
· Of 84 with 13
· 22 had t(4;14)
· 62 did not
· Median survivals
· 26.8 vs. 18.8 mos p=.001
· PFS
· 12.9 vs. 8.2 p=0.001
Impact of 13 in t(4;14)+ patients
· Conversely, in the t(4;14)+ cohort the
presence or absence of 13 had no
impact on survival 19.4 vs. 18.8 mos
· In t(4;14)+ 13 is found in 85% but
only in 49% of t(4;14)- patients p<.001
· In deletion 13 presence of 4;14
shortens survival but in 4;14, deletion
13 had no effect
TTP of 13q patients based on t(11;14)
status N=84
1.0
0.9
P=0.001
0.8
0.7
t(4;14)- 12.9 mos
0.6
0.5
Surviving 0.4
0.3
0.2
0.1
t(4;14)+ 8.2 mos
0.0
0
10 20 30 40 50 60 70 80 90 100 110 120 130
response duration
Survival of 13q patients based on
t(11;14) status N=84
1.0
0.9
P=0.001
0.8
0.7
0.6
t(4;14)- 26.8 mos
0.5
Surviving 0.4
0.3
0.2
t(4;14)+ 18.8 mos
0.1
0.0
0
10 20 30 40 50 60 70 80 90 100 110 120 130
survival from BMT
Conclusions
· t(4;14) provides important prognostic
information
· The information compliments the LI & 2-
Microglobulin
· In this model 13 by FISH does not add
additional prognostic power to that provided
by t(4;14) or 2-M
· We were unable to confirm superior
outcome of t(11;14)
· -17p13 identifies a poor prognostic category

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