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NEOPLASIA
Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected
by fluorescence in situ hybridization: incidence increases from MGUS to
relapsed myeloma and is related to prognosis and disease progression
following tandem stem-cell transplantation
Ichiro Hanamura, James P. Stewart, Yongsheng Huang, Fenghuang Zhan, Madhumita Santra, Jeffrey R. Sawyer, Klaus Hollmig,
Maurizio Zangarri, Mauricio Pineda-Roman, Frits van Rhee, Federica Cavallo, Bart Burington, John Crowley, Guido Tricot, Bart Barlogie,
and John D. Shaughnessy Jr
Using fluorescence in situ hybridization
we investigated amplification of chromosome band 1q21 (Amp1q21) in more than
500 untreated patients with monoclonal
gammopathy of undetermined significance (MGUS; n ⴝ 14), smoldering multiple myeloma (SMM; n ⴝ 31), and newly
diagnosed MM (n ⴝ 479) as well as 45
with relapsed MM. The frequency of
Amp1q21 was 0% in MGUS, 45% in SMM,
43% in newly diagnosed MM, and 72% in
relapsed MM (newly diagnosed versus
relapsed MM, P < .001). Amp1q21 was
detected in 10 of 12 patients whose disease evolved to active MM compared with
4 of 19 who remained with SMM (P < .001).
Patients with newly diagnosed MM with
Amp1q21 had inferior 5-year event-free/
overall survival compared with those lacking Amp1q21 (38%/52% versus 62%/78%,
both P < .001). Thalidomide improved
5-year EFS in patients lacking Amp1q21
but not in those with Amp1q21 (P ⴝ .004).
Multivariate analysis including other major predictors revealed that Amp1q21 was
an independent poor prognostic factor.
Relapsed patients who had Amp1q21 at
relapse had inferior 5-year postrelapse
survival compared with those lacking
Amp1q21 at relapse (15% versus 53%,
P ⴝ .027). The proportion of cells with
Amp1q21 and the copy number of 1q21
tended to increase at relapse compared
with diagnosis. Our data suggest that
Amp1q21 is associated with both disease
progression and poor prognosis. (Blood.
2006;108:1724-1732)
© 2006 by The American Society of Hematology
Introduction
High-dose therapy with autologous stem cell transplantation has
become the standard of care in multiple myeloma (MM), especially
for relatively young patients, and can prolong survival1-4; however,
survival ranges from a few months to more than 10 years.1-4
Monoclonal gammopathy of undetermined significance (MGUS),
an asymptomatic plasma-cell dyscrasia seen in approximately 3%
of persons over 60 years of age, and smoldering MM (SMM) share
virtually all the genetic lesions seen in MM, yet MGUS rarely
converts to overt MM requiring therapy.5-7
Karyotype abnormalities in plasma-cell dyscrasias are common
and highly complex and contain random events that might have
little effects on tumor pathogenesis. Cytogenetic analyses, including fluorescence in situ hybridization (FISH), have contributed to
identification of nonrandom chromosomal aberrations in plasmacell dyscrasias8-12 and to a better understanding of the clinical
implications of these chromosomal aberrations in MM.13-15 Deletion of chromosome 13 (del(13)), hypodiploidy, and t(4;14), which
leads to ectopic overexpression of FGFR3 and MMSET, are known
to be associated with a poor prognosis.
Previous studies based on comparative genomic hybridization
(CGH) have revealed that unbalanced chromosomal structural
changes were present in almost all plasma-cell dyscrasias, and
chromosomal gains of 1q consistently involved the 1q21 region in
MM.16-18 We have reported previously that the gain of 1q21 can occur as
isochromosomes, duplications, or jumping translocations in MM.19,20
The gain of the 1q21 region, which is one of the most recurrent
chromosomal aberrations in MM and other cancers,21-24 has been
speculated to be linked to a poor prognosis in MM.25 However, a
comprehensive analysis of the prognostic significance of gains
and/or amplifications of 1q21 (henceforth referred to as Amp1q21)
has never been evaluated in a large cohort of newly diagnosed MM.
In addition, the association of the genetic events underlying the
conversion of MGUS and SMM to MM and its eventual fatal
progression are not completely understood.
Here we provide evidence that Amp1q21 is associated with a
poor prognosis in newly diagnosed MM and a shortened
postrelapse survival and may be central to progression of
plasma-cell dyscrasias.
From the Donna D. and Donald M. Lambert Laboratory of Myeloma Genetics,
Myeloma Institute for Research and Therapy, University of Arkansas for
Medical Sciences, Little Rock; and Cancer Research and Biostatistics,
Seattle, WA.
An Inside Blood analysis of this article appears at the front of this issue.
Submitted March 15, 2006; accepted April 25, 2006. Prepublished online as
Blood First Edition Paper, May 16, 2006; DOI 10.1182/blood-2006-03-009910.
Reprints: John D. Shaughnessy Jr, Donna D. and Donald M. Lambert
Laboratory of Myeloma Genetics, University of Arkansas for Medical Sciences, 4301 W. Markham St. #776, Little Rock, AR 72205; shaughnessyjohn@
uams.edu.
Supported by National Institutes of Health grants CA55819 (J.D.S., B.B.) and
CA97513 (J.D.S.) by the Fund to Cure Myeloma.
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734.
The online version of this article contains a data supplement.
© 2006 by The American Society of Hematology
1724
BLOOD, 1 SEPTEMBER 2006 䡠 VOLUME 108, NUMBER 5
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BLOOD, 1 SEPTEMBER 2006 䡠 VOLUME 108, NUMBER 5
GAIN OF 1q21 IN PLASMA-CELL DYSCRASIAS
1725
Fluorescence in situ hybridization
Patients, materials, and methods
Patients
Samples for this study were obtained from patients with MGUS (n ⫽ 14),
SMM (n ⫽ 31), newly diagnosed MM (n ⫽ 479), and relapsed MM
(n ⫽ 45). The baseline characteristics of 524 untreated patients with
MGUS, SMM, and newly diagnosed MM are summarized in Table 1.
Newly diagnosed and relapsed MM patients in this study were all enrolled
in University of Arkansas research protocol UARK 98-026 (Total Therapy
226,27), which is a melphalan-based tandem autologous stem cell transplantation protocol that randomized 668 patients to receive or not receive
thalidomide. A total of 479 of 668 patients with newly diagnosed MM had
interphase FISH results of 1q21 available at baseline; 189 of the 668
patients enrolled on the Total Therapy 2 trial were not analyzed due to either
lack of sufficient samples and/or poor quality after hybridization.
At the time of analysis, in the 479 newly diagnosed patients we
analyzed, the median follow-up of surviving patients was 53 months (range,
25 to 89) and there were 297 events and 207 deaths in this subset. In 45
relapsed patients who had interphase FISH results of 1q21 available at
relapse, the median follow-up of postrelapse survival was 17 months
(range, 0.3 to 78). The median follow-up of patients with MGUS and SMM
was 22 months (range, 1 to 88) and 47 months (range, 1 to 123),
respectively. The Institutional Review Board of the University of Arkansas
for Medical Sciences approved the research studies, and all subjects
provided written informed consent approving use of their samples for
research purposes.
Cell lines
Human myeloma cell lines NCU-MM1, OCI-MY5, U266, EJM, SK-MM1,
JJN3, H929, ANBL6, RPMI8226, KMS12PE, MM_M1, OCI-MY1, XG7,
Delta47, L363, XG1, OPM1, CAG, UTMC2, OPM2, ARP1, KMS11, and
FR4 were cultured in RPMI 1640 with 10% fetal bovine serum (FBS),
100 IU/mL penicillin, and 100 mg/mL streptomycin at 37°C in 5% CO2 and
10 ng/mL human recombinant interleukin-6 (R&D Systems, Minneapolis,
MN) when needed.
Statistical analyses
Table 1. Baseline patient characteristics
No. of patients/total no. (%)
Characteristics
MGUS
SMM
MM
5/14 (36)
7/31 (23)
115/479 (24)
Female sex
6/14 (43)
17/31 (55)
205/479 (43)
White race
12/14 (86)
29/31 (94)
429/479 (90)
IgA subtype
0/8 (0)
6/26 (23)
120/475 (25)
B2M level 4 mg/L or more
1/14 (7)
0/31 (0)
146/479 (30)
Age 65 y or older
Bacterial artificial chromosomes (BACs) at 1q21 (RP11-307C12) and at
1q31 (RP11-32D17) were purchased from BAC/PAC Resources (Oakland,
CA). Chromosome 13 ploidy was evaluated with a BAC clone for marker
D13S31 mapping to 13q14. IGH break-a-part probe (Vysis, Downers
Grove, IL) was used to analyze for the presence of 14q32 translocations. All
probes were directly labeled by nick translation with Spectrum-Green
and/or Spectrum-Red (Vysis). BAC and P1 artificial chromosome (PAC)
clone information was obtained through the website of the National Center
for Biotechnology Information28 (NCBI), and the probes were confirmed to
map to the precise chromosome bands using metaphase spreads from the
peripheral-blood lymphocytes from healthy donors.
Interphase FISH with cytoplasmic immunoglobulin light chain staining
was performed according to the procedure described previously.13 A
detailed protocol for probe production and hybridization can be found in
Documents S1-S3 (available on the Blood website; see the Supplemental
Materials link at the top of the online article). Briefly, the probes were
hybridized along with AMCA-labeled antibodies to ␬ or ␭ immunoglobulin
light chains (Vector Laboratories, Burlingame, CA) to cytospin preparations of mononuclear cells from bone marrow aspirates by Ficoll separation
fixed with ethanol (Figure S1A). The slides were stored at ⫺20°C until
FISH analyses were performed. Interphase FISH signals were evaluated in
at least 100 clonal plasma cells (mainly 100) in each patient. If at least 3
copies were seen in at least 20% of clonal plasma cells, it was considered
evidence of gain/amplification. To investigate effects of the magnitude of
Amp1q21 on clinical outcomes and each category, Amp1q21 was divided
into 2 categories: (1) 3 copies of 1q21 (the percentage of cells with at least 4
copies was seen in less than 20% of clonal plasma cells) and (2) at least 4
copies of 1q21 (the percentage of cells with at least 4 copies was seen in at
least 20% of clonal plasma cells.
A detailed account of the FISH data for 1q21 on all samples presented in
this study can be found in Table S4.
Chromosome preparation for metaphase FISH analysis in human
myeloma cell lines was performed according to the standard procedure as
described previously.29 Briefly, cells were cultured in log phase, treated
with colcemid (final concentration, 005 mg/mL) for 30 minutes, harvested
with hypotonic potassium chloride (0.075M KCl), and fixed with methanol/
glacial acetic acid (3:1; cornoy solution). Metaphase FISH analyses were
performed according to the manufacturer’s protocol (Vysis) (Figure S1B-C).
CRP level 4 mg/L or more
0/14 (0)
3/31 (10)
43/479 (9)
Creatinine level 2 mg/dL or more
2/13 (15)
0/30 (0)
51/475 (11)
LDH level 190 IU/L or more
5/14 (36)
3/31 (10)
148/479 (31)
ALB level less than 3.5 g/dL
0/12 (0)
3/31 (10)
157/463 (34)
HGB level less than 10 g/dL
0/14 (0)
3/31 (10)
135/479 (28)
CA
1/13 (8)
1/29 (3)
148/440 (34)
Hyperdiploidy*
0/13 (0)
1/29 (3)
79/440 (18)
Hypodiploidy*
1/13 (8)
0/29 (0)
52/440 (12)
PC in BM aspirate 33% or more
0/14 (0)
6/28 (21)
183/402 (46)
PC in BM biopsy 33% or more
0/14 (0)
0/28 (0)
193/402 (48)
To convert ␤2-microglobulin level from milligrams per liter to nanomoles per liter,
multiply milligrams per liter by 85. To convert creatinine level from milligrams per
deciliter to micromoles per liter, multiply milligrams per liter by 88.4. To convert
albumin and hemoglobin levels from grams per deciliter to grams per liter, multiply
grams per deciliter by 10.
B2M indicates serum ␤2-microglobulin; CRP, C-reactive protein; LDH, serum
lactate dehydrogenase; ALB, serum albumin; HGB, hemoglobin; CA, cytogenetic
abnormalities defined by G banding; PC, plasma cells; BM, bone marrow.
*Ploidy was defined by G banding.
Event-free survival (EFS) and overall survival (OS) distributions were
estimated using the Kaplan-Meier method, and differences among survival
curves were analyzed by the log-rank test. The ␹2 test and the Fisher exact
test were used to test for the independence of categories. Multivariate
analysis of EFS and OS adjusted for the effects of Amp1q21 for other
predictors was performed using the Cox proportional hazards regression
model. P values below .05 were considered significant.
Gene-expression profiling
Gene-expression profiling using the Affymetrix U133 Plus 2.0 microarray
(Affymetrix, Santa Clara CA), was performed on CD138-purified plasma
cells from bone marrow aspirates of newly diagnosed patients as described
previously.30 Chromosomal translocations involving the IGH locus result in
transcriptional hyperactivation of protooncogenes such as CCND1, CCND3,
FGFR3/MMSET, c-MAF, and MAFB.31 These translocation events are
detectable as “spiked” expression by microarray analysis.30
Results
Correlation of Amp1q21 and clinical and biologic features
in newly diagnosed MM
Table 2 summarizes patient characteristics according to Amp1q21
in newly diagnosed MM. Interphase FISH analysis for 1q21 was
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1726
BLOOD, 1 SEPTEMBER 2006 䡠 VOLUME 108, NUMBER 5
HANAMURA et al
Table 2. Baseline patient characteristics according to Amp1q21
in newly diagnosed MM
Table 4. Summary of interphase FISH results for 1q21 in patients
with newly diagnosed and relapsed MM according to the copy
number of 1q21
No. of patients/total no. (%)
Characteristics
Age, 65 y or older
Female sex
No Amp1q21*
Amp1q21
P
62/274 (23)
53/205 (26)
.413
107/274 (39)
98/205 (48)
.055
No. of patients/total no. (%)
1 copy of 1q21
At
diagnosis
At
relapse
P
7/479 (0.01)
0/45 (0)
ND
⬍ .001
White race
241/274 (88)
188/205 (92)
.184
IgA subtype
53/274 (19)
67/201 (33)
⬍ .001
2 copies of 1q21
267/479 (56)
12/45 (27)
B2M level 4 mg/L or more
68/274 (25)
78/205 (38)
.002
3 copies of 1q21
117/479 (24)
13/45 (29)
.507
CRP level 4 mg/L or more
24/274 (9)
19/205 (9)
.847
At least 4 copies of 1q21
88/479 (18)
20/45 (44)
⬍ .001
Creatinine level 2 mg/dL or more
24/272 (9)
27/203 (13)
.119
LDH level 190 IU/L or more
67/274 (24)
81/205 (40)
⬍ .001
ALB level less than 3.5 g/dL
80/265 (30)
77/198 (39)
.050
HGB level less than 10 g/dL
63/274 (23)
72/205 (35)
.004
CA
66/253 (26)
82/187 (44)
⬍ .001
Hyperdiploidy†
35/253 (14)
44/187 (24)
.009
Hypodiploidy†
16/253 (6)
36/187 (19)
⬍ .001
.133
PC in BM aspirate 33% or more
107/251 (43)
76/151 (50)
PC in BM biopsy 33% or more
105/246 (43)
88/156 (56)
.007
37/252 (15)
67/184 (36)
⬍ .001
del(13)‡
Focal bone lesions by MRI, 3 or
140/265 (53)
107/196 (55)
.708
ISS stage 1
more
140/265 (53)
73/202 (36)
⬍ .001
ISS stage 2
83/265 (31)
73/202 (36)
.274
ISS stage 3
42/265 (16)
56/202 (28)
.002
MRI indicates magnetic resonance imaging; other abbreviations are explained in
Table 1.
To convert ␤2-microglobulin level from milligrams per liter to nanomoles per liter,
multiply milligrams per liter by 85. To convert creatinine level from milligrams per
deciliter to micromoles per liter, multiply milligrams per liter by 88.4. To convert
albumin and hemoglobin levels from grams per deciliter to grams per liter, multiply
grams per deciliter by 10.
*Amp1q21: at least 3 copies of 1q21 defined by interphase FISH.
†Ploidy was defined by G banding.
‡del(13): at least 80% of cells with up to 1 copy of D13S31 by interphase FISH.
successful in 479 of 668 patients who enrolled in Total Therapy 2.
Patient characteristics of 189 newly diagnosed patients who did not
have FISH results of 1q21 at baseline were similar to those of 479
patients who had FISH results (data not shown). In 479 patients
with newly diagnosed MM, there were 7 patients with 1 copy of
1q21, 267 with 2 copies of 1q21, and 205 with at least 3 copies of
1q21 (Amp1q21) (Tables 3-4). Patients with Amp1q21 tended to
have a high incidence of IgA subtype (P ⬍ .001), high level of
B2M (P ⫽ .002), high level of LDH (P ⬍ .001), low level of HGB
(P ⫽ .004), high incidence of abnormal karyotypes defined by
Table 3. Summary of interphase FISH results of Amp1q21 in
patients with MGUS, SMM, newly diagnosed MM, and relapsed MM
Amp1q21 (%)
MGUS
Total
0/14 (0)
Progression, ⫹
0/1 (0)
Progression, ⫺
0/13 (0)
SMM
Total
14/31 (45)
Progression, ⫹
10/12 (83)
Progression, ⫺
4/19 (21)
MM
At diagnosis
At relapse
205/479 (43)
33/45 (72)
The median follow-up of patients with MGUS and SMM was 22 months (range,
1 to 88) and 47 months (range, 1 to 123), respectively. P ⬍ .001 for SMM progression,
⫹, versus SMM progression, –. P ⬍ .001 for MM at diagnosis versus MM at relapse.
P ⫽ .002 for total MGUS versus total MM.
NA indicates not applicable.
ND indicates not done.
G banding (P ⬍ .001), high incidence of hyperdiploidy (P ⫽ .009),
high incidence of hypodiploidy (P ⬍ .001), high percentage of
plasma cells in bone marrow by biopsy (P ⫽ .007), high incidence
of del(13) defined by FISH (P ⬍ .001), low frequency of stage 1
(P ⬍ .001), and high frequency of stage 3 (P ⫽ .002) based on the
International Staging System (ISS) compared with those lacking
Amp1q21 in newly diagnosed MM (Table 2).
Frequency of Amp1q21 in MGUS and SMM and transition
from SMM to MM
Amp1q21 was detected in 0 of 14 (0%) patients with MGUS
compared with 14 of 31 (45%) patients with SMM (P ⫽ .002)
(Table 3). Among patients with SMM, Amp1q21 was detected in 10
of 12 (83%) patients who evolved to having active MM compared
with 4 of 19 (21%) patients who remained with SMM (P ⬍ .001)
(Table 3). Frequency of Amp1q21 in MGUS was significantly low
compared with that in newly diagnosed MM (MGUS versus newly
diagnosed MM, 0 of 14 [0%] versus 205 of 479 [43%], P ⫽ .001),
and frequency of Amp1q21 in SMM was similar with newly
diagnosed MM (SMM versus newly diagnosed MM, 14 of 31
[45%] versus 205 of 479 [43%], P ⫽ .797) (Table 3).
Prognostic relevance of Amp1q21 in newly diagnosed MM
Among newly diagnosed MM, the estimated median time to
complete remission (CR) or near CR (nCR) was 9 months in those
lacking Amp1q21. The estimated 2-year CR or nCR rate in this
group was 73%. In patients with Amp1q21, the median time to CR
or nCR was 81⁄4 months and the 2-year CR or nCR rate was 67%
(Figure 1A). The log-rank P value was .11, and the hazard ratio for
CR or nCR among those with Amp1q21 compared with those
lacking Amp1q21 was 1.2, likely reflecting the modestly shorter
estimated median time to CR or nCR among those with Amp1q21.
The 5-year EFS in patients lacking Amp1q21 was 62% compared with 38% in patients with Amp1q21 (P ⬍ .001), and 5-year
OS in patients lacking Amp1q21 was 78% compared with 52% in
patients with Amp1q21 (P ⬍ .001) (Figure 1B).
In a multivariate analysis, including abnormal karyotypes
detected by G banding, B2M 297.5 nM (3.5 mg/L) or more, ALB
less than 35 g/L (3.5 g/dL), LDH 190 IU/L or more, and del(13)
defined by interphase FISH, Amp1q21 represented an independent
poor prognostic factor for both EFS and OS in newly diagnosed
MM (Table 5).
Among newly diagnosed patients with Amp1q21, there were
117 patients with 3 copies of 1q21 and 88 with at least 4 copies of
1q21 (Table 4). Patients with 3 copies of 1q21 had inferior EFS and
OS compared with those with up to 2 copies of 1q21 (5-year
EFS/OS, 3 copies versus up to 2 copies, 40%/53% versus
62%/78%, both P ⬍ .001) (Figure S2). The 5-year EFS and OS
were similar among patients with 3 copies and at least 4 copies of
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BLOOD, 1 SEPTEMBER 2006 䡠 VOLUME 108, NUMBER 5
GAIN OF 1q21 IN PLASMA-CELL DYSCRASIAS
1727
Figure 1. Incidence and rates of remission and EFS and OS based on the presence or absence of Amp1q21. (A) The proportion of cases within the group with no
Amp1q21 (n ⫽ 267) and Amp1q21 (n ⫽ 201) achieving CR or nCR is plotted over time. (B) A Kaplan-Meier analysis of EFS (left) and OS (right) is displayed in relation to no
Amp1q21 (n ⫽ 274) or Amp1q21 (n ⫽ 205). CI indicates confidence interval.
1q21 (5-year EFS/OS, 3 copies versus at least 4 copies, 40%/53%
versus 38%/50%, P ⫽ .344 for EFS and P ⫽ .453 for OS).
Adding thalidomide to control therapy improved 5-year EFS in
patients lacking Amp1q21 but did not in those with Amp1q21
(5-year EFS, patients lacking Amp1q21 treated with thalidomide
versus those treated without thalidomide, 73% versus 54%,
P ⫽ .004; patients with Amp1q21 treated with thalidomide versus
those treated without thalidomide, 42% versus 37%, P ⫽ .392)
(Figure 2A). Adding thalidomide did not improve OS in either
patients lacking Amp1q21 or those with Amp1q21 (P ⫽ .226,
P ⫽ .638, respectively) (Figure 2B).
Correlation between Amp1q21, 14q32 translocations, oncogene
spikes, and cytogenetic abnormalities
We also observed that the incidence of t(14q32) detected by
interphase FISH was similar among patients with Amp1q21 and
lacking Amp1q21 in patients who had FISH results for 1q21 and
t(14q32) (P ⫽ .155, n ⫽ 127, Table 6). On the other hand, in
patients who had both 1q21 FISH results and microarray data
(n ⫽ 253), those with Amp1q21 had a high incidence of spiked
expression of c-MAF or FGFR3/MMSET compared with those
lacking Amp1q21 (P ⫽ .002, P ⬍ .001, respectively), whereas an
incidence of spiked expression of CCND1 in patients with Amp1q21
was low compared with those lacking Amp1q21 (P ⬍ .001) (Table
7). Among the 40 patients with FGFR3/MMSET spikes, the 3-year
EFS was 64% in those lacking Amp1q21 and 27% in those with
Amp1q21 (P ⫽ .010) (Figure 3A). The 3-year OS in those lacking
Amp1q21 was 77% and, in those with Amp1q21, 59% (P ⫽ .212)
(Figure 3A). Among the 54 patients with CCND1 spikes, the
presence or absence of Amp1q21 did not significantly alter the
3-year EFS or OS (Figure 3B). The lack of sufficient numbers of
cases with CCND3, MAF, and MAFB spikes precluded their
analysis here.
The presence of CAs in an MM karyotype is a powerful
negative predictor of survival in MM. Patients with no CA but
having Amp1q21 had an inferior outcome relative to those with no
CA and lacking Amp1q21 (P ⬍ .001) (Figure 4). This effect was
more pronounced in those patients with CA. Those with Amp1q21
in the context of CA had an inferior far worse outcome compared
with those with CA but lacking this abnormality (P ⬍ .001) (Figure 4).
Correlation of Amp1q21 between newly diagnosed and
relapsed MM and postrelapse survival
The frequency of Amp1q21 at relapse was significantly higher than
in newly diagnosed MM (relapsed versus newly diagnosed MM, 33
of 45 [72%] versus 205 of 479 [43%], P ⬍ .001) (Table 3).
The mean and median percentage of myeloma cells with
Amp1q21 at relapse tended to be higher than those in newly
diagnosed MM (mean/median, relapsed versus newly diagnosed
MM, 65%/88% versus 36%/7%) (Figure 5). The frequency of
patients with at least 4 copies of 1q21 at relapse was significantly
higher than that at diagnosis (20 of 45 [44%] versus 88 of 479 [8%],
P ⬍ .001), whereas the frequency of patients with 3 copies of 1q21
was similar at relapse and diagnosis (13 of 45 [29%] versus 117 of
479 [24%], P ⫽ .507) (Table 4). The patients with at least 4 copies
of 1q21 tended to have a high percentage of myeloma cells with
Table 5. Multivariate Cox proportional hazards analysis in newly diagnosed MM
Event-free survival
Overall survival
%
HR
95% CI
P
HR
95% CI
P
Amp1q21
42
1.86
1.34, 2.57
⬍ .001
1.78
1.19, 2.68
.005
del(13)*
24
1.49
1.03, 2.14
.034
1.64
1.05, 2.56
.031
CA
34
1.51
1.09, 2.09
.014
1.82
1.22, 2.71
.003
B2M level, 3.5 mg/L or more
34
1.35
0.96, 1.88
.081
1.35
0.90, 2.04
.145
LDH level, 190 IU/L or more
29
1.39
0.99, 1.95
.057
1.46
0.96, 2.22
.074
ALB level, less than 3.5 g/dL
34
1.32
0.96, 1.81
.083
1.45
0.99, 2.13
.059
A total of 389 of the 479 newly diagnosed myeloma patients with 1q21 FISH results had complete data for multivariate proportional hazards regression analysis in this
study.
To convert ␤2-microglobulin level from milligrams per liter to nanomoles per liter, multiply milligrams per liter by 85. To convert albumin level from grams per deciliter to
grams per liter, multiply grams per deciliter by 10.
HR indicates hazard ratio; other abbreviations are explained in Table 1.
*del(13) was defined by interphase FISH using a D13S31 probe. If at least 80% of clonal plasma cells had at least 1 signal of the D13S31 probe, the tumor was considered
positive for deletion in this analysis. We also provide a multivariate analysis using a 20% cut point in Table S3.
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1728
BLOOD, 1 SEPTEMBER 2006 䡠 VOLUME 108, NUMBER 5
HANAMURA et al
Figure 2. EFS and OS among patients with newly
diagnosed MM according to Amp1q21 and adding
thalidomide or not. A Kaplan-Meier analysis of EFS
(left) and OS (right) is displayed in relation to no Amp1q21
(up to 2 copies of 1q21, n ⫽ 124) or Amp1q21 (3 or more
copies of 1q21, n ⫽ 102) in patients treated with a
regimen containing thalidomide and in relation to no
Amp1q21 (n ⫽ 150) or Amp1q21 (n ⫽ 103) in patients
treated with a regimen without thalidomide. Thal⫹ indicates patients treated with thalidomide; Thal–, patients
treated without thalidomide.
Amp1q21 compared with those with 3 copies of 1q21 at both
diagnosis and relapse (at diagnosis, 73% versus 92%; at relapse,
72% versus 97%; Table 8).
Twenty-eight patients had 1q21 FISH results available both at
diagnosis and relapse. In these 28 patients, as shown in Figure 6, 27
had the same or greater copy numbers of 1q21 at relapse compared
with those at diagnosis.
Among 45 relapsed patients who had 1q21 FISH results at
relapse and receiving various salvage therapies, patients with
Amp1q21 at relapse had inferior 5-year postrelapse survival
compared with those lacking Amp1q21 at relapse (15% versus
53%, P ⫽ .027) (Figure 7). Among 33 relapsed patients with
Amp1q21 at relapse, 5-year postrelapse survival in patients with at
least 4 copies of 1q21 at relapse was 0% compared with 32% in
those with 3 copies of 1q21 at relapse (P ⫽ .060) (Figure 7).
Incidence of Amp1q21 in human myeloma cell lines
Amp1q21 was detected by metaphase FISH in 21 of 23 (91%)
human myeloma cell lines. The copy number of 1q21 was the same
or greater compared with that of 1q31 in all 23 human myeloma
cell lines tested (Figure S1B-C; Table S1). Importantly, the cell line
OCI-MY5, which has 2 copies of the 1q21 region, harbors a
deletion of the p arm and much of the q arm and juxtaposition of the
1q21 region to a nonhomologous chromosome (data not shown).
Discussion
MM is a plasma-cell malignancy that can sometimes be preceded
by MGUS or SMM, and MM mostly is incurable, which can be
linked to drug resistance. The precise mechanisms of initiation and
progression of MM are poorly understood; however, MM is
thought to develop through a multistep process, including a
genomic instability, through which clonal evolution may occur. It
has been suggested that gain of the 1q21 region, which is one of
the most recurrent chromosomal aberrations in MM, is related to
an advanced phenotype of MM and therefore may be associated
with disease progression.25 Support for this concept is borne by
our observation of an increased incidence of Amp1q21 in
disease progression. Amp1q21 was observed in 0% in MGUS,
45% in SMM, 43% in newly diagnosed MM, 72% in relapsed
MM, and 91% in human myeloma cell lines. Amp1q21 was
associated with inferior EFS and OS in MM, a higher risk of
transition of SMM to active MM, and a shortened postrelapse
survival. Our data are consistent with previous reports on
frequency of Amp1q21 in newly diagnosed MM based on FISH
and CGH25,32-34 and with a report showing positive correlation
between presence of Amp1q21 by CGH and transition from
SMM to active MM.35
Among 479 patients with newly diagnosed MM, 205 patients
(43%) with Amp1q21 had a high incidence of abnormal,
hypodiploid, and hyperdiploid karyotypes and del(13) by FISH,
IgA predominance, high-level B2M and LDH, a low level of
HGB and, finally, a poor prognosis compared with those lacking
Amp1q21. Patients with Amp1q21 seem to constitute a unique
subgroup of MM.
We also observed that the incidence of Amp1q21 was similar to
that of no Amp1q21 in patients with t(14q32), which is not
consistent with a previous report.32 Interestingly, while Amp1q21
was only present in 28% of cases with CCND1 spikes, this anomaly
Table 7. Correlation of spiked expression of 5 protooncogenes
associated with recurrent translocations in MM according
to Amp1q21 in newly diagnosed MM
Table 6. Correlation of t(14q32) and Amp1q21 in newly
diagnosed MM
No. of patients/total no. (%)
No Amp1q21
Amp1q21
t(14q32)
45/80 (56)
No t(14q32)
Total
No. of patients/total no. (%)
P
Spikes
Frequency, %
No Amp1q21
Amp1q21
P
35/80 (44)
.155
21.3
39/54 (72)
15/54 (28)
⬍ .001
33/47 (70)
14/47 (30)
⬍ .001
CCND1
ND
78/127 (61)
49/127 (39)
NA
A total of 127 patients had both FISH results for 1q21 and IGH translocations in
newly diagnosed MM enrolled in Total Therapy 2. The presence of t(14q32) was
defined by interphase FISH using the commercial IGH break-a-part probes (Vysis). If
at least 20% of clonal plasma cells had split signals of IGH probes, it was considered
the presence of t(14q32).
NA indicates not applicable.
CCND3
2.4
3/6 (50)
3/6 (50)
MAFB
2.4
2/6 (33)
4/6 (67)
.567
c-MAF
2.4
0/6 (0)
6/6 (100)
.002
MMSET
15.8
10/40 (25)
30/40 (75)
⬍ .001
Others
55.7
85/141 (60)
56/141 (40)
ND
Total
NA
139/253 (55)
114/253 (45)
NA
ND indicates not done; NA, not applicable.
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BLOOD, 1 SEPTEMBER 2006 䡠 VOLUME 108, NUMBER 5
GAIN OF 1q21 IN PLASMA-CELL DYSCRASIAS
1729
Figure 3. EFS and OS among patients with newly
diagnosed MM according to the presence or absence
of common recurrent translocations and Amp1q21. A
Kaplan-Meier analysis of EFS (left) and OS (right) in
patients with MMSET spikes (A) or CCND1 spikes (B)
according to the presence or absence of Amp1q21. Note
that the difference in median follow-up of this group of
patients is different from the overall group because
microarray profiling was initiated after Total Therapy 2
had started.
was present in 100% of cases with c-MAF spikes and 75% of cases
with FGFR3/MMSET spikes. These findings are similar to those
seen with del(13) in which there is a strong positive correlation
with MM with t(14;16) or t(4;14), whereas del(13) is infrequent in
those with t(11;14).5,31 Together these data would indicate that
Figure 4. OS among patients with newly diagnosed MM according to cytogenetic abnormalities and Amp1q21. A Kaplan-Meier analysis of OS in 440 patients
who had both 1q21 FISH results and karyotype data by G banding according to the
presence or absence of cytogenetic abnormalities and Amp1q21.
Amp1q21 tends to occur in MM cells with dysregulated expression
of c-MAF or FGFR3/MMSET after illegitimate IGH translocations,
probably as a progression event. Survival analysis of the effect of
Amp1q21 was evaluated in patients with FGFR3/MMSET spikes, a
known high-risk feature. Although Amp1q21 was found to negatively affect EFS in this group, OS was not significantly different
Figure 5. The proportion of cells with Amp1q21 at diagnosis and relapse. The
proportion of cells with Amp1q21 is indicated by the height of the bar on the y-axis.
The proportion of cells with 3 and with 4 or more copies of 1q21 in each sample is
indicated by blue and red, respectively. A total of 479 newly diagnosed MM and 45
relapsed MM samples are ordered from the lowest to highest proportion of cells with
Amp1q21 from left to right in each group on the x-axis. The mean/median
percentages of cells with Amp1q21 at diagnosis and relapse were 36%/65% and
7%/88%, respectively.
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1730
BLOOD, 1 SEPTEMBER 2006 䡠 VOLUME 108, NUMBER 5
HANAMURA et al
Table 8. The mean percentage of cells with Amp1q21 according to
the copy number of 1q21 at diagnosis and relapse
No.
Mean % of cells
with Amp1q21
At diagnosis
Up to 2 copies of 1q21
274
3
3 copies of 1q21
117
73
88
92
479
36
At least 4 copies of 1q21
Total
At relapse
Up to 2 copies of 1a21
12
3
3 copies of 1q21
13
72
At least 4 copies of 1q21
20
97
Total
45
65
between those with and without Amp1q21. However, the effect on
OS is consistent with the results for EFS, and analysis of a larger
sample might reveal a significant difference. An important reason
that this happens is that less than one quarter of patients with
FGFR3/MMSET spikes lack Amp1q21, so it is hard to get a large
enough sample to estimate their lower death rate. The fact that most
FGFR3/MMSET spike–positive cases harbor Amp1q21 is highly
significant and seems to be in need of a biologic explanation.
Perhaps the cases lacking Amp1q21 represent an early stage of the
disease and Amp1q21 will emerge at relapse. Longitudinal studies
will be needed to address this hypothesis. Consistent with this
concept, the proportion of MM cells with Amp1q21 ranged widely
at diagnosis. The copy number of 1q21 in each patient and the
mean and median percentage of cells with Amp1q21 all tended to
increase at relapse compared with diagnosis, which may suggest
that the clonal evolution of Amp1q21 and/or the clonal selection
and expansion of MM cells with Amp1q21 occur during therapy.
An important aim of future research in our group is to understand if
genes located in the 1q21 region, whose expression is gene dosage
dependent, promote resistance to chemotherapy.
Patients with at least 4 copies of 1q21 at diagnosis tended to
have a higher percentage of cells with Amp1q21 (Table S2) and
showed an initially more aggressive clinical course than those with
3 copies of 1q21. However, patients with at least 4 copies of 1q21 at
diagnosis had similar 5-year EFS and OS compared with those with
3 copies of 1q21 (Figure S2), whereas patients with at least 4 copies
of 1q21 at relapse had an inferior postrelapse survival compared
Figure 7. Postrelapse survival of MM patients enrolled in Total Therapy 2
according to Amp1q21 and the copy number of 1q21 at relapse. Kaplan-Meier
analysis of postrelapse survival is shown in relation to no Amp1q21 (up to 2 copies of
1q21, n ⫽ 12) or Amp1q21 (3 or more copies of 1q21, n ⫽ 33) at relapse (top) and up
to 2 copies (n ⫽ 12), 3 copies (n ⫽ 13), or 4 or more copies (n ⫽ 20) of 1q21 at
relapse (bottom) determined by interphase FISH. At the time of analysis, the median
follow-up of a postrelapse survival was 17 months (range, 0.3 to 78) in this analysis.
with those with 3 copies of 1q21. This may suggest that
myeloma cells with at least 4 copies of 1q21 are potentially
associated with a more malignant and drug-resistant phenotype
than those with 3 copies of 1q21 but that, during therapy,
residual cells with 3 copies of 1q21 can continue to increase
1q21 copy numbers and thus become as malignant as those with
at least 4 copies of 1q21 at diagnosis.
Figure 6. The proportion of cells with Amp1q21 and
the copy number of 1q21 in each patient at diagnosis
and relapse in paired patients. Twenty-eight patients
had 1q21 FISH results available at both diagnosis and
relapse. The proportion of cells with Amp1q21 is indicated
by the height of the bar on the y-axis. Each sample is
represented by a left and right bar indicating the proportion of cells with Amp1q21 at diagnosis and relapse,
respectively. The proportion of cells with 3 and with 4 or
more copies of 1q21 in each sample is indicated by blue
and red, respectively. The numbers below each patient
number indicate the copy number of 1q21 at diagnosis
and relapse. Sample ID is same as that in Table S4.
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BLOOD, 1 SEPTEMBER 2006 䡠 VOLUME 108, NUMBER 5
GAIN OF 1q21 IN PLASMA-CELL DYSCRASIAS
Despite the fact that Amp1q21 is present in up to 50% of
newly diagnosed patients, we have shown that in multivariate
analysis including other major predictors Amp1q21 was an
independent adverse prognostic factor. However, among patients with ISS stage 3, OS was similar between those with
Amp1q21 and lacking Amp1q21, whereas patients with Amp1q21
had inferior OS among patients with ISS stage 1 and 2 (Figure
S3); therefore, Amp1q21 is a poor prognostic marker in patients
whose B2M is less than 467.5 nM (5.5 mg/L).
We have reported that adding thalidomide to high-dose melphalan-based tandem autotransplantations improved EFS but did not
improve OS due to a shorter postrelapse survival in the thalidomide
group.27 In this study, we demonstrated that adding thalidomide
improved EFS in patients lacking Amp1q21, whereas 5-year EFS
in patients with Amp1q21 was similar between those who were
treated with thalidomide and without thalidomide. Adding thalidomide did not improve OS either in patients lacking Amp1q21 or
with Amp1q21. The molecular reason underlying this finding is
currently not clear, but the finding suggests that the presence of
Amp1q21 might be an important determinant for stratifying
patients to receive or not receive thalidomide.
The cellular and molecular mechanisms of Amp1q21 are not
well understood but are thought to involve decondensation of
pericentromeric heterochromatin in MM and lymphoma.19,20,36
There also remains a question as to whether Amp1q21 is a cause or
a consequence of disease progression. Amp1q21 may reflect
chromosomal instability, which is related to tumor progression,
which is usually through silencing tumor suppressor genes.37
However, activation of a protooncogene caused by increased gene
dosage accompanying chromosomal instability can also play an
important role in tumor development and progression. Evidence of
high-level amplification of 1q21 in MM20,38 suggests that the
amplification may be of pathogenic significance related to increased copy number and a concomitant increase in the expression
of gene(s) within this region. We recently reported on the highresolution mapping of a 10 Mb amplicon at 1q21,39 and we and
others have reported on deregulated expression of candidate genes
1731
in the 1q21 region in MM and other cancers.38-51 However, none of
these candidate genes, with the exception of RAB25, has been
investigated in animal models. Moreover, the possible combined
effect of multiple candidate genes has not been demonstrated or
considered. In the future, precise direct functional analyses of each
candidate gene using animal models and analyses of mass effects of
several genes in the same amplicon on tumor development will be
required to establish the association of genes within the amplicon
as causal in MM progression.
In conclusion, we have demonstrated that Amp1q21 was an
independent adverse prognostic marker in newly diagnosed MM
treated with autotransplantations, associated with a shortened
postrelapse survival and a higher risk of transition from SMM to
MM. In addition, we have demonstrated that the proportion of cells
with Amp1q21 and the copy number of 1q21 tended to increase at
relapse compared with diagnosis, and adding thalidomide improved EFS in patients lacking Amp1q21 at diagnosis but did not in
patients with Amp1q21 at diagnosis. Our data suggest that Amp1q21
is associated with a malignant phenotype in MM and may be
central to progression of plasma-cell dyscrasias. Clarification of the
mechanism(s) that cause Amp1q21 and identification of possible
responsible gene(s) in this region might provide more precise
insight into the natural history of myeloma and possible novel
targets for future therapies in MM and in other cancers.
Acknowledgments
We thank members of the Donna D. and Donald M. Lambert
Laboratory of Myeloma Genetics for technical assistance: Ermin
Tian, Christopher Adams, Christopher Crane, Adam Hicks, Bob
Kordsmeier, Christopher Randolph, Steven McMorran, Owen
Stephens, Ryan Williams, Yan Xaio, and Hongwei Xu. We thank Dr
Michael Kuehl for providing many of the myeloma cell lines. We
extend a special thanks to all patients, their caregivers, and
referring physicians for making this work possible.
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2006 108: 1724-1732
doi:10.1182/blood-2006-03-009910 originally published
online May 16, 2006
Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias
detected by fluorescence in situ hybridization: incidence increases from
MGUS to relapsed myeloma and is related to prognosis and disease
progression following tandem stem-cell transplantation
Ichiro Hanamura, James P. Stewart, Yongsheng Huang, Fenghuang Zhan, Madhumita Santra,
Jeffrey R. Sawyer, Klaus Hollmig, Maurizio Zangarri, Mauricio Pineda-Roman, Frits van Rhee,
Federica Cavallo, Bart Burington, John Crowley, Guido Tricot, Bart Barlogie and John D.
Shaughnessy, Jr
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