|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
Prepublished online as a Blood First Edition Paper on January 16, 2003; DOI 10.1182/blood-2002-09-2873.
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Myeloma Institute for Research and Therapy,
University of Arkansas for Medical Sciences, Little Rock, AR; Cancer
Research and Biostatistics (CRAB), Seattle, WA;
Universitats-HNO-Klinik, Erlangen, Germany; St Vincent Comprehensive
Cancer Center, New York, NY; Medical College of Wisconsin, Milwaukee,
WI; Hackensack University Medical Center, Hackensack, NJ; Dana Farber
Cancer Center, Harvard Medical Center, Boston, MA; and Greenebaum
Cancer Center, University of Maryland, Baltimore, MD.
Metaphase cytogenetic abnormalities (CAs), especially of chromosome
13 (CA 13), confer a grave prognosis in multiple myeloma even
with tandem autotransplantations as applied in Total Therapy I, which
enrolled 231 patients between 1989 and 1994. With a median follow-up of
almost 9 years, the prognostic implications of all individual
CAs, detected prior to treatment and at relapse, were investigated. Among all CAs and standard prognostic factors examined prior to therapy, only hypodiploidy and CA 13 (hypo-13 CA), alone or
in combination, were associated with shortest event-free survival and
overall survival (OS). The shortest postrelapse OS was observed with hypo-13 CA, which was newly detected in 18 of all 28 patients presenting with this abnormality at relapse. Superior prognosis was
associated with the absence of any CA at both diagnosis and relapse
(10-year OS, 40%). The lack of independent prognostic implications of
other CAs points to a uniquely aggressive behavior of hypo-13 CA
(present in 16% of patients at diagnosis). With the use of microarray
data in 146 patients enrolled in Total Therapy II,
overexpression of cell cycle genes distinguished CA from no CA,
especially in cases of del(13) detected by interphase
fluorescence in situ hybridization (FISH). FISH 13, resulting
in a haploinsufficiency of RB1 and other genes mapping to
chromosome 13, as well as activation of IGF1R, appears to
have an amplifying effect on cell cycle gene expression, thus providing
a molecular explanation for the dire outcome of patients with CA 13 compared with those with other CAs.
(Blood. 2003;101:3849-3856) The clinical course of patients with multiple
myeloma (MM) is best predicted by the presence of certain cytogenetic
abnormalities (CAs), in the context of both standard and high-dose
therapies.1-5 A particularly high risk for early treatment
failure and short survival has been associated with CA 13, whether
detected by traditional metaphase karyotype analysis (present
in 15% of patients)1-4,6 or, more recently, by
interphase fluorescence in situ hybridization (FISH) (present
in 50%).5,7-9 As part of Total Therapy I (TT I),10 a phase 2 pilot program using melphalan-based tandem
autotransplantations with curative intent, cytogenetic studies were
performed prospectively at baseline and as part of virtually all
subsequent bone marrow examinations. In this report, we have
investigated, along with standard prognostic factors (SPFs), the
individual contributions of every chromosome abnormality present prior
to initiation of TT I and at follow-up, especially at relapse. With the
use of gene expression profiles (GEPs) and FISH available in
146 patients prospectively enrolled in Total Therapy II (TT II)
(successor protocol to TT I),11 the uniquely adverse
implications, especially of CA 13, were examined by comparing GEP data
in the 4 patient subsets defined by FISH 13 and CA.
Total Therapy I
Patient demographics.
Between 1989 and 1994, 231 patients with symptomatic or
progressive MM were enrolled in TT I; 155 were entirely
untreated and the remainder had previously received one cycle of
standard chemotherapy or dexamethasone. Patient demographics are
summarized in Table 1 along with
frequencies of first and second transplantations. Stringently defined
complete remission (CR) (intent-to-treat) was achieved by 38%
of patients. The median follow-up of living patients approaches
9 years.
Statistical considerations. The large number of CAs under investigation and the low incidence rate of many of the CAs make it desirable to reduce the list of CAs considered for analysis with outcome variables, so as not to end up with results that may be spurious and irreproducible. To divide the list of specific CAs into subsets, we first calculated the minimum incidence rate necessary for a given CA to achieve adequate statistical power (at least 80%) to distinguish a meaningful effect size in a univariate test for prognostic effect. For this purpose, we chose as an effect size a hazard ratio of at least 3.0 when making comparisons with patients without a given abnormality. Since the hazard ratio for presence of any CA was slightly below 2.0, an increase to 3.0 seemed appropriate, so as to identify specific CAs with comparatively higher prognostic importance. With the use of these assumptions, the minimum incidence rate was calculated to be 5% (approximately 10 or more patients) in the overall population who had baseline cytogenetics (n = 222). Outcome definitions. Overall survival (OS) was calculated as the time from initiation of TT I to death from any cause or last contact. Event-free survival (EFS) was calculated as the time from initiation of TT I to either progression of disease, death from any cause, or last contact. Secondary end points of interest were also explored. Analysis methods. Survival curves were estimated by the product-limit method13 and compared by means of the log-rank test.14 Cox proportional hazards regression15 was used to assess the influence of CAs and SPFs on survival outcomes. Logistic regression was used to relate cytogenetics and SPFs to dichotomous outcomes. Multivariate models were constructed by means of backward stepwise regression methods. All univariately significant covariates were included in the stepwise selection. Total Therapy II In an effort to determine the molecular mechanisms underlying the poor prognosis of CA 13 MM, we resorted to data available in 146 patients treated according to TT II. These included conventional cytogenetics, FISH, and GEPs.Fluorescence in situ hybridization. Detailed methods for triple-color interphase FISH have been described.11,16 The percentage of clonotypic plasma cells with evidence of monosomy of chromosome 13 was determined for the 146 cases with gene-expression profiling data. For purposes of this study, monosomy of chromosome 13 (referred to as "FISH 13") was observed in 79 (54%) of 146 cases. Monosomy was defined as at least 50% of cytoplasmic immunoglobulin-positive (cIg+) cells exhibiting only one signal for each of 4 probes, D13S31, D13S221, D13S285, and BRCA2, spanning the long arm of chromosome 13. A total of 67 cases had no evidence of deletion (fewer than 20% cIg+ cells with deletion of any probe). These patients were deemed to lack chromosome 13 deletion (referred to as "no FISH 13"). Conventional G-band cytogenetics were performed on all 146 samples by means of conventional methodologies.12 CAs were present in 64 cases (44%) and no CAs in 82 cases.Gene expression profiles. Detailed protocols for plasma cell isolation and microarray hybridization have been previously described.17,18 Briefly, plasma cells were isolated from bone marrow aspirates of 146 newly diagnosed MM patients enrolled into the clinical trial TT II (successor program to TT I) after written informed consent was obtained, in keeping with institutional policies. Total RNA was isolated, converted to biotinylated cRNA, and hybridized to the U95av2 GeneChip microarrays interrogating approximately 12 000 genes (Affymetrix, Santa Clara, CA). Scanned output files were analyzed with GeneChip 5.0.1 software (Affymetrix). Arrays were scaled to an average intensity of 1500 and analyzed independently. GeneChip data analysis.
All data used in our analysis were derived from Affymetrix
Microarray Suite 5.0. GeneChip 5.0 output files are given (1) as a
signal that represents the difference between the intensities of the
sequence-specific perfect-match probe set and the mismatch probe set,
or (2) as a detection of present or absent as determined by the
GeneChip 5.0 algorithm. Signals were transformed by the log base 2. Statistical analysis of the data was performed with the SPSS 10.0 (Chicago IL); Significance Analysis of Microarray (SAM) software
package,19 and PAM R package.20 To filter
genes that tend to be absent in all samples, those with
Incidence of and associations among CAs CAs were observed at pretreatment evaluation in 33%. Table 2 lists, per individual chromosome, the specific CA encountered along with its frequency. Trisomies present in at least 10% of patients involved chromosomes 3, 5, 7, 9, 11, 15, 19, and 21. Monosomies and deletions, usually of the q arm, affected predominantly chromosomes 6 (6%), 13 (13%), 16 (10%), and 22 (6%). Hypodiploidy, as defined by Smadja et al,5 was present in 11% (Table 3). Abnormalities typical of MDS within the context of a typical MM signature karyotype (MM-MDS) were present in 7%, including 5, 5q, 7, 7q, +8, del(20q), and
t(1;7)(q10;p10).
On average, 6 chromosomes were altered in any given CA (median, 6 chromosomes; range, 1-13 chromosomes). We performed clustering analysis
of specific CAs present in at least 10 patients prior to the start of
protocol therapy (Figure 1).
Of patients with hypodiploid CAs at baseline, 58% also had
del(13), and 71% had any abnormality of chromosome 13 (including del(13), del(13q), and t(13q)) (CA 13), indicating a high degree of
correlation (r = 0.61). Of the total of 222 patients, 16%
had either CA 13 or hypodiploidy ("hypo-13 CA"). Translocations of 11q and 14q, representing a t(11;14)(q13;q32) in 10 (59%) patients, clustered closely at diagnosis. The actual frequency of
specific CAs (no CA, hypo-13 CA, other CAs [which are
prognostically relevant]) during the disease course is depicted in
Figure 2A. Presumably as a result of
suppression by effective therapy especially of non-CA 13 and
nonhypodiploid clones, progressively fewer CAs were noted during the
first 2 years after initiation of TT I, and CAs slowly
increased thereafter. Eventually, at 8 years, the distribution of CAs
was similar to that at baseline. The cumulative CA frequency reached
58% at 10 years, including more than a doubling of hypo-13 CA from
16% to 36% (Figure 2B).
CAs and SPFs Strong associations were noted between some prognostically relevant SPFs and CA 13 as well as hypodiploid CAs, including Durie-Salmon stage III, -2-microglobulin (B2M) level of
at least 345 nM (at least 4 mg/L); lactic dehydrogenase (LDH) level of
at least 190 U/L; hypoalbuminemia (albumin level of at least
35 g/L [at least 3.5 g/dL]); hemoglobin level no higher than
100 g/L (no higher than 10 g/dL); and bone marrow
plasmacytosis of at least 50%. All of these represent
features of high tumor burden or aggressive disease. IgA was
more frequent with MM-MDS (odds ratio [OR], 5.4), whereas C-reactive
protein (CRP) of at least 4 mg/L was associated with
t(1q). Translocations of 11q (t(11q)) predicted for age of at least 65 years and B2M of at least 345 nm (at least 4 mg/L).
CAs and clinical outcome EFSs and OSs of the entire patient population are depicted in Figure 3: 20% of patients remain event-free and 36% alive, with 10-year estimates of EFS and OS of 17% (± 5%) and 31% (± 7%), respectively. The median CR duration is 2.8 years after the onset of CR (median time to CR, 9 months), with 29% (± 10%) of patients in continuous CR at 8 years.
Both EFS and OS differed markedly when examined in the context of
individual CAs and of CA groups (Figure
4). The poor prognosis of patients
presenting with CA 13, and del(20) as well as CA 1 is
apparent. When examined in the context of group assignment, hypodiploid
CAs had the shortest OS. On multivariate analysis, hypodiploid-13 CA,
present in 16% of patients prior to therapy, was the only
unfavorable parameter among all CAs that was independently associated with both short EFS and OS (Table
4). Both an LDH of at least 190 U/L
and renal failure (creatinine level
Importantly, hypodiploid-13 CA, also in a time-dependent setting,
remained an independent adverse feature for both EFS and OS along with
CRP, attesting to its robust clinical implications (Figure
5).
Superior EFS and OS was enjoyed by 67% of patients lacking any CA whereas patients with hypodiploid-13 CA had the worst outcome; those with other CAs had EFS and OS not significantly different from the clinical course of patients without CAs. Thus, median OS exceeded EFS by more than 2-fold, both in the absence of CA and in case of other CAs; in contrast, the hypodiploid-13 CA group showed a median postrelapse OS of less than 1 year. The 7 patients with t(11;14) without concomitant CA 13 or hypodiploid CAs had median EFS and OS of 25 and 54 months, respectively, not different from the entire group of other CAs. We next investigated the clinical implications of CAs detected on
follow-up bone marrow examination. According to univariate time-dependent models to assess the instantaneous hazard of CA detection subsequent to initiation of therapy, both EFS and OS were
significantly compromised whenever CA 13 or hypodiploid CAs were
detected (data not shown). According to multivariate analysis, the
presence of either CA 13 or hypodiploid CAs at relapse was associated
with short subsequent OS. Thus, postrelapse OS was longest (5 years) in
the absence of CA and progressively shortened to 2 years with other CAs
and was only 9 months in case of hypodiploid-13 CA (Figure
6).
Further examination of both baseline and relapse CAs in the 118 patients with available cytogenetic information (Table
5) revealed superior postrelapse OS of 79 months among the 51 patients lacking CA at both time points; followed
by 39 months in the 21 patients with CAs only at baseline.
Of the 28 patients experiencing relapse with hypodiploid-13 CA, 12 had presented with no CA and 6 with other CAs at diagnosis (Table 5). Conversely, of the 21 with baseline hypodiploid-13 CA, 11 had no CA at relapse, none had other CAs, and 10 had experienced a recurrence of hypodiploid-13 CA. The remaining 15 patients of the original 36 who had this abnormality at baseline did not have cytogenetic examinations on follow-up, mostly owing to rapid death upon documentation of relapse. Gene expression profiles The data presented so far point to a unique prognostic role of certain baseline CAs (CA 13, hypodiploid CAs) (Figures 4-5). On multivariate analysis of individual CAs and CA groups, CA 13, but not hypodiploidy, was the dominant adverse feature for both OS and EFS (data not shown). Prospective concurrent evaluation of CAs, FISH for detection of del(13) (FISH 13), and GEPs are being conducted as part of TT II. Among approximately 50% of patients with FISH 13, only those also harboring CA 13 had inferior survival whereas those with FISH 13 but without CA 13 fared as well as patients lacking FISH 13; plasma cell-labeling index was not an independent prognosticator.11 We reasoned that in vitro MM cell division, required for metaphase CA to be detected, was a critical biologic feature of stroma cell-independent growth shared by CA 13 and other CAs.11 Availability of GEP data in 146 TT II patients along with CA and FISH 13 status provided the opportunity to determine the molecular basis for the uniquely grave prognosis associated with FISH 13/CA (CA 13) compared with all other groups, especially no FISH 13/CA.FISH 13 versus no FISH 13.
From a training set of 47 samples with FISH 13 and 51 samples without FISH 13, 36 genes were identified at the
intersection of data sets from the CAs versus no CAs.
The sequential Distinguishing 4 MM subgroups on the basis of FISH 13 and CA.
To demonstrate that expression levels of these genes could discriminate
4 cytogenetic subgroups (no FISH 13/no CA; no FISH 13/CA; FISH 13/no
CA; and FISH 13/CA), the so-called "shrunken centroids"
method20 was used with 30 genes. These included the top 20 differentially expressed genes in a comparison between FISH 13/CA and
no FISH 13/no CA as well as 10 genes identified by MSDA in the
comparison of FISH 13 versus no FISH 13. Figure 7 shows centroids (average expression of
each gene) in each of the 4 patient subgroups.
The values represent the difference between the individual group centroid and the overall centroid (all 146 cases). The 45 patients with FISH 13/no CA were uniformly characterized by underexpression of both cell cycle- and chromosome 13-related genes. By contrast, the 30 patients in the no FISH 13/CA group showed mainly right-sided bars, indicative of relative overexpression of both cell cycle- and chromosome 13-related genes. The third group of 37 patients with no FISH 13/no CA was characterized by expression of chromosome 13 genes (right-sided bars) and underexpression of all cell cycle genes (left-sided bars). Finally, the 34 patients with FISH 13/CA represented the mirror image of the previous group in that all cell cycle genes were particularly strongly expressed (more so than in the no FISH 13/CA group) and chromosome 13 genes were profoundly underexpressed (more so than in the FISH 13/no CA group). Thus, it appears that, collectively, FISH 13/CA is characterized by a net overexpression of all cell cycle genes and underexpression of chromosome 13 genes. The mirror image is seen in the no FISH 13/no CA group. However, the underexpression of cell cycle-related genes does not match their overexpression in the FISH 13/CA group. In either comparison, FISH 13 appears to be a modulator of cell cycle gene expression.
Total Therapy I The profound CA complexity typical of MM has made it difficult to account for individual prognostic contributions of certain CAs, especially when one considers that 49 specific abnormalities occurred in fewer than 5% of patients and that 93% coexisted. Here, we confirm the adverse implications of CA 13 and hypodiploid CAs, confirming 2 recent other studies.5,21 Thus, among 475 patients enrolled in tandem transplantation trials prior to 2000 (including previously treated and refractory MM), Fassas et al21 noted that CA 13, regardless of ploidy status, and a hypodiploid karyotype without CA 13 both imparted poor outcome after high-dose therapy. The more frequent association of CA 13 with hypodiploidy as compared with other CAs (65% versus 30%; P < .001) is in keeping with results of the cluster analysis of this report (Figure 1). The prognosis of patients with other CAs, including t(11;14)(q13;q32), was superior to that observed with CA 13 or hypodiploidy and, in fact, was not significantly inferior to the outcome of patients with no CAs (Figure 5).Although perhaps anticipated, this is the first documented observation in MM of an inferior prognosis associated with the detection of CAs, particularly of CA 13 and hypodiploid CAs, at relapse or, according to time-dependent instantaneous hazard models, at any time after initiation of primary therapy. Best outcomes were noted when CAs were absent both before treatment and after transplantation; prognosis was worst when hypodiploidy or CA 13 was present at relapse, regardless of pretreatment findings (Figure 6). Indeed, of the 28 patients with hypodiploid-13 CA at relapse, 18 represented new CAs (12 without CA at baseline, 6 with other CAs) (Table 5). In the first instance (no CA at baseline and hypodiploid-13 CA at relapse), del(13) or hypodiploidy was probably present at diagnosis if interphase FISH had been applied. In the second scenario (hypodiploid-13 CA at relapse with other CAs at diagnosis), CA 13 or hypodiploidy was acquired in addition to other CAs rather than representing a separate clone, consistent with clonal evolution in some patients. Together with nearly doubling by 10 years, in a cumulative account of CA incidence (including hypodiploid-13 CA), these findings are consistent with a progressively more proliferative nature of advancing MM. It is conceivable that eventually all patients with MM develop CA when one considers the universal presence of genetic abnormalities detectable by interphase FISH22 with a 50% incidence of del(13).11 Thus, "no CA" probably reflects normal hematopoiesis, whereas CAs, as a result of successful in vitro MM cell division, distinguish a high-risk subtype that proliferates independently of the bone marrow microenvironment, consistent with an autocrine growth mechanism.11 Associations between the presence of CA and short telomere length/high telomerase activity in highly purified MM cells are consistent with telomere erosion as an important molecular mechanism in the generation of the observed genomic instability.23 Interphase FISH has recently been applied to the setting of high-dose therapy by French MM investigators.24 Applying probes pertinent to the detection of translocations involving the IGH locus at 14q32 and del(13), the authors reported, among patients with CAs, the worst prognosis in those exhibiting t(4;14)(p16;q32) and superior outcome in cases of t(11;14)(q13;q32). Intermediate prognosis in the remainder was limited to patients without del(13). The median survival of those with FISH del(13), however, almost 4 years after a single transplantation, is significantly longer than the 2.5 years observed after tandem transplantation for patients with CA 13 as reported in this study. A worse prognosis in cases of metaphase-defined CA 13 was noted in a head-to-head comparison of interphase FISH del(13) and standard cytogenetics in patients receiving TT II.11 Indeed, the OS of patients with FISH 13 but without CA 13 was indistinguishable from that of patients without FISH 13 (regardless of the presence or absence of CA). Total Therapy II GEP analysis showed significant elevation of a large panel of cell cycle/DNA metabolism genes both in the CA versus no CA and the FISH 13 versus no FISH comparisons (Figure 7). Thus, the expression patterns of these genes could be used to segregate discrete cytogenetic subgroups so that MM with CA and FISH 13 had highly elevated expression levels of cell cycle genes in comparison with CA without FISH 13. The deletion of chromosome 13 not only results in a haploinsufficiency of specific chromosome 13 genes (eg, GTF2F2, TSC-22, and RB1) but also is associated with an amplification of the expression of cell cycle genes. The reason for this effect is not known, but probably reflects a larger proliferative proportion of CD138 cells, thus accounting for the dire outcome of CA 13 (FISH 13/CA) MM in comparison with other CAs (no FISH 13/CA) MM.On the basis of the integration of molecular and conventional cytogenetics, patient outcome, and global GEPs, we hypothesize that one consequence of del(13) is haploinsufficiency of the tumor suppressor gene RB1. This hypothesis is supported by recent data linking an increased risk of human colon cancer and murine lymphoma to haploinsufficiency of BLM.25,26 Importantly, this model can account for a lack of inactivating mutations in the remaining allele of RB1 and the inability, even after exhaustive searches, to identify a definitive tumor suppressor gene mapping to 13q14.27-29 Given the important influence of DNA repair defects in cancer development, it is noteworthy that 2 excision repair genes, ERCC5 (excision repair cross-complementing rodent repair deficiency, complementation group 5 gene, mapping to chromosome 13) and ERCC1 (mapping to chromosome 19q13.2), were significantly down-regulated in patients with FISH 13 (data not shown), suggesting that loss of these genes could lead to the genomic instability and poor outcome in FISH 13 disease. Interestingly, insulin-like growth factor I receptor (IGF1R), a powerful growth-signaling receptor in MM,30-32 represents the only gene significantly up-regulated (turned on) in FISH 13 MM. We have recently reported that both normal and MM bone marrow plasma cells express IGF1, whereas tonsil-derived plasma cells and tonsillar B cells do not.18 Thus, we speculate that activation of IGF1R (absent on normal plasma cells) on MM cells could create an autocrine growth-signaling loop in FISH 13 MM. Elevated expression of cyclin B1 (CCNB1) and the mitotic cyclin-specific ubiquitin-conjugating enzyme E2C (UBE2C) in MM with CAs, and especially in FISH 13/CA, is notable. Since mutant UBE2C results in stabilization of both cyclin A and cyclin B, arrests cells in M phase, and inhibits the onset of anaphase, destruction of mitotic cyclins by ubiquitin-dependent proteolysis seems required for cells to complete mitosis and enter interphase of the next cell cycle.33 UBE2C-mediated ubiquitination is also involved in inactivation of CDC2 (hyperactivated in FISH 13/CA) and in sister chromatid separation, 2 processes normally coordinated during exit from mitosis. We speculate that a therapeutic strategy of treating patients with FISH 13/CA might be to inhibit UBE2C function. Overexpression of topoisomerase II (TOP 2A) in the FISH 13/CA MM subgroup suggests that inhibitors of these gene products may be especially effective in this poor prognosis group. In fact, etoposide has been a component of both TT I (EDAP [etoposide, dexamethasone, adriamycin, and cisplatin] regimen) and TT II (DCEP [dexamethasone, cyclophosphamide, etoposide, and cisplatin] for induction and consolidation) ("Patients and methods"). Finally, the recent observation of marked antitumor activity of the proteasome inhibitor PS-34134-36 and allogeneic T cells37 justify rapid implementation of clinical trials of these therapeutic approaches in this high-risk MM entity. Thus, molecular profiling may prove useful in moving toward the rational development of new combination therapies. We conclude that the perceived shortcomings of metaphase karyotyping, that is, its dependence on in vitro mitotic activity in a typically hypoproliferative malignancy such as MM, has helped reveal a possible microenvironment-independent, more aggressive disease subtype with distinct molecular genetic features. Consequently, we strongly recommend that metaphase karyotyping be performed as part of the staging of all patients with MM at both diagnosis and relapse.
The authors gratefully acknowledge the outstanding contributions of Caran Swanson, BS; Bonnie Jenkins, RN, OCN; and the Nursing and Support Staff of the Myeloma Institute for Myeloma and Therapy. This work is dedicated to a lasting memory of Fabio Bertarelli, who died in 1998 at the age of 73 after an 11-year battle with MM, exhibiting high-risk cytogenetics abnormalities. His intellectual, emotional, and fiscal contributions were critical to the establishment of the Arkansas Myeloma Program.
Submitted September 20, 2002; accepted January 4, 2003.
Prepublished online as Blood First Edition Paper, January 16, 2003; DOI 10.1182/blood-2002-09-2873.
Supported in part by CA55819 from the National Cancer Institute, Bethesda, MD.
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.
Reprints: Bart Barlogie, Director, Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, 4301 West Markham, Slot 816, Little Rock, AR 72205; e-mail: barlogiebart{at}uams.edu.
1.
Tricot G, Barlogie B, Jagannath S, et al.
Poor prognosis in multiple myeloma is associated only with partial or complete deletions of chromosome 13 or abnormalities involving 11q and not with other karyotype abnormalities.
Blood.
1995;86:4250-4256
2.
Tricot G, Sawyer J, Jagannath S, et al.
The unique role of cytogenetics in the prognosis of patients with myeloma receiving high dose therapy and autotransplants.
J Clin Oncol.
1997;15:2659-2666
3.
Desikan R, Barlogie B, Sawyer J, et al.
Results of high dose therapy for 1000 patients with multiple myeloma: durable complete remissions and superior survival in the absence of chromosome 13 abnormalities.
Blood.
2000;95:4008-4010 4. Seong C, Delasalle K, Hayes K, et al. Prognostic value of cytogenetics in multiple myeloma. Br J Haematol. 1998;101:189-195[CrossRef][Medline] [Order article via Infotrieve].
5.
Smadja N, Bastard C, Brigaudeau C, Leroux D, Fruchart C.
Hypodiploidy is a major prognostic factor in multiple myeloma.
Blood.
2001;98:2229-2238
6.
Tricot G, Spencer T, Sawyer J, et al.
Predicting long-term (
7.
Zojer N, Koenigsberg R, Ackermann J, et al.
Deletion of 13q14 remains an independent adverse prognostic variable in multiple myeloma despite its frequent detection by interphase fluorescence in situ hybridization.
Blood.
2000;95:1925-1930
8.
Facon T, Avet-Loiseau H, Guilerm G, et al.
Chromosome 13 abnormalities identified by FISH analysis and serum beta-2-microglobulin produce a powerful myeloma staging system for patients receiving high dose therapy.
Blood.
2001;97:1566-1571
9.
Fonseca R, Harrington D, Oken M, et al.
Biological and prognostic significance of interphase fluorescence in situ hybridization detection of chromosome 13 abnormalities (
10.
Barlogie B, Jagannath S, Desikan R, et al.
Total therapy with tandem transplants for newly diagnosed multiple myeloma.
Blood.
1999;93:55-65 11. Shaughnessy J, Tian E, Sawyer J, et al. Prognostic impact of cytogenetic and interphase fluorescence in situ hybridization-defined chromosome 13 deletion in multiple myeloma: early results of total therapy II. Br J Haematol. 2003;120:44-52[CrossRef][Medline] [Order article via Infotrieve]. 12. Sawyer J, Waldron J, Jagannath S, Barlogie B. Cytogenetics findings in 200 patients with multiple myeloma. Cancer Genet Cytogenet. 1995;82:41-49[CrossRef][Medline] [Order article via Infotrieve]. 13. Kaplan EL, Meier P. Nonparametric estimation for incomplete observations. J Am Stat Assoc. 1958;53:457-481[CrossRef]. 14. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep. 1966:163-170. 15. Cox DR. Regression models and life-tables (with discussion). J Royal Stat Soc, Series B. 1972;34:187-220.
16.
Shaughnessy J, Tian E, Sawyer J, et al.
High incidence of chromosome 13 deletions in multiple myeloma detected by multiprobe interphase FISH.
Blood.
2000;96:1505-1511
17.
Zhan F, Hardin J, Kordsmeier B, et al.
Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance and normal bone marrow plasma cells.
Blood.
2002;99:1745-1757
18.
Zhan F, Tian E, Bumm K, Smith R, Barlogie B, Shaughnessy J Jr.
Gene expression profiling of human plasma cell differentiation and classification of multiple myeloma based on similarities to distinct stages of late-stage B-cell development.
Blood.
2003;101:1128-1140
19.
Tusher V, Tibshirani R, Chu G.
Significance analysis of microarrays applied to the ionizing radiation response.
Proc Natl Acad Sci U S A.
2001;98:5116-5121
20.
Tibshirani R, Hastie T, Narasimhan B, Chu G.
Diagnosis of multiple cancer types by shrunken centroids of gene expression.
Proc Natl Acad Sci U S A.
2002;99:6567-6572 21. Fassas A, Spencer T, Sawyer J, et al. Both hypodiploidy and deletion of chromosome 13 independently confer poor prognosis in multiple myeloma. Br J Haematol. 2002;118:1041-1047[CrossRef][Medline] [Order article via Infotrieve].
22.
Drach J, Schuster J, Nowotny H, et al.
Multiple myeloma: high incidence of chromosomal aneuploidy as detected by interphase fluorescence in situ hybridization.
Cancer Res.
1995;55:3854-3859 23. Wu K, Orme L, Shaughnessy J, Bumm K, Barlogie B, Moore M. Telomerase and telomere length in multiple myeloma: correlations with disease heterogeneity, cytogenetic status and overall survival. Blood. In press.
24.
Moreau P, Facon T, Leleu Z, et al.
for the Intergroupe Francophone du Myeloma. Recurrent 14q32 translocations determine the prognosis of multiple myeloma especially in patients receiving intensive chemotherapy.
Blood.
2002;100:1579-1583
25.
Gruber SB, Ellis NA, Scott KK, et al.
BLM heterozygosity and the risk of colorectal cancer.
Science.
2002;297:2013
26.
Goss KH, Risinger MA, Kordich JJ, et al.
Enhanced tumor formation in mice heterozygous for Blm mutation.
Science.
2002;297:2051-2053
27.
Calin GA, Dumitru CD, Shimizu M, et al.
Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia.
Proc Natl Acad Sci U S A.
2002;99:15524-15529
28.
Mabuchi H, Fujii H, Calin G, et al.
Cloning and characterization of CLLD6, CLLD7, and CLLD8, novel candidate genes for leukemogenesis at chromosome 13q14, a region commonly deleted in B-cell chronic lymphocytic leukemia.
Cancer Res.
2001;61:2870-2877
29.
Migliazza A, Bosch F, Komatsu H, et al.
Nucleotide sequence, transcription map, and mutation analysis of the 13q14 chromosomal region deleted in B-cell chronic lymphocytic leukemia.
Blood.
2001;97:2098-2104
30.
Georgii-Hemming P, Wiklund HJ, Ljunggren O, Nilsson K.
Insulin-like growth factor I is a growth and survival factor in human multiple myeloma cell lines.
Blood.
1996;88:2250-2258 31. Ge N-L, Rudikoff S. Insulin-like growth factor I is a dual effector of multiple myeloma cell growth. Blood. 2002;96:2856-2861.
32.
Qiang Y-W, Kopantzev E, Rudikoff S.
Insulin-like growth factor-I signaling in multiple myeloma: downstream elements, functional correlates, and pathway cross-talk.
Blood.
2002;99:4138-4146
33.
Townsley F, Aristarkhov A, Beck S, Hershko A, Ruderman J.
Dominant-negative cyclin-selective ubiquitin carrier protein E2-C/UbcH10 blocks cells in metaphase.
Proc Natl Acad Sci U S A.
1997;94:2362-2367
34.
LeBlanc R, Catley LP, Hideshima T, et al.
Proteasome inhibitor ps-341 inhibits human myeloma cell growth in vivo and prolongs survival in a murine model.
Cancer Res.
2002;62:4996-5000
35.
Hideshima T, Mitsiades C, Akiyama M, et al.
Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341.
Blood.
2003;101:1530-1534 36. Zangari M, Barlogie B, Prather J, et al. Marked activity also in del 13 multiple myeloma of PS 341 and subsequent thalidomide in a setting of resistance to post-autotransplant salvage therapies [abstract]. Blood. 2002;100:387a[CrossRef].
37.
Badros A, Barlogie B, Morris C, et al.
High response rate in refractory and poor-risk multiple myeloma after allotransplantation using a nonmyeloablative conditioning regimen and donor lymphocyte infusions.
Blood.
2001;97:2574-2579
© 2003 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  B. Barlogie, J. D. Shaughnessy Jr., and J. Crowley Duration of Survival in Patients with Myeloma Treated with Thalidomide N. Engl. J. Med., July 10, 2008; 359(2): 210 - 212. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Haessler, J. D. Shaughnessy Jr., F. Zhan, J. Crowley, J. Epstein, F. van Rhee, E. Anaissie, M. Pineda-Roman, M. Zangari, K. Hollmig, et al. Benefit of Complete Response in Multiple Myeloma Limited to High-Risk Subgroup Identified by Gene Expression Profiling Clin. Cancer Res., December 1, 2007; 13(23): 7073 - 7079. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Zhan, S. Colla, X. Wu, B. Chen, J. P. Stewart, W. M. Kuehl, B. Barlogie, and J. D. Shaughnessy Jr CKS1B, overexpressed in aggressive disease, regulates multiple myeloma growth and survival through SKP2- and p27Kip1-dependent and -independent mechanisms Blood, June 1, 2007; 109(11): 4995 - 5001. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Mulligan, C. Mitsiades, B. Bryant, F. Zhan, W. J. Chng, S. Roels, E. Koenig, A. Fergus, Y. Huang, P. Richardson, et al. Gene expression profiling and correlation with outcome in clinical trials of the proteasome inhibitor bortezomib Blood, April 15, 2007; 109(8): 3177 - 3188. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Shaughnessy Jr, F. Zhan, B. E. Burington, Y. Huang, S. Colla, I. Hanamura, J. P. Stewart, B. Kordsmeier, C. Randolph, D. R. Williams, et al. A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1 Blood, March 15, 2007; 109(6): 2276 - 2284. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Zhan, B. Barlogie, V. Arzoumanian, Y. Huang, D. R. Williams, K. Hollmig, M. Pineda-Roman, G. Tricot, F. van Rhee, M. Zangari, et al. Gene-expression signature of benign monoclonal gammopathy evident in multiple myeloma is linked to good prognosis Blood, February 15, 2007; 109(4): 1692 - 1700. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Agnelli, S. Bicciato, S. Fabris, L. Baldini, F. Morabito, D. Intini, D. Verdelli, A. Callegaro, F. Bertoni, G. Lambertenghi-Deliliers, et al. Integrative genomic analysis reveals distinct transcriptional and genetic features associated with chromosome 13 deletion in multiple myeloma Haematologica, January 1, 2007; 92(1): 56 - 65. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Zhan, Y. Huang, S. Colla, J. P. Stewart, I. Hanamura, S. Gupta, J. Epstein, S. Yaccoby, J. Sawyer, B. Burington, et al. The molecular classification of multiple myeloma Blood, September 15, 2006; 108(6): 2020 - 2028. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Barlogie, G. Tricot, E. Rasmussen, E. Anaissie, F. van Rhee, M. Zangari, A. Fassas, K. Hollmig, M. Pineda-Roman, J. Shaughnessy, et al. Total therapy 2 without thalidomide in comparison with total therapy 1: role of intensified induction and posttransplantation consolidation therapies Blood, April 1, 2006; 107(7): 2633 - 2638. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. B. Batchu, A. M. Moreno, S. M. Szmania, G. Bennett, G. C. Spagnoli, S. Ponnazhagan, B. Barlogie, G. Tricot, and F. van Rhee Protein Transduction of Dendritic Cells for NY-ESO-1-Based Immunotherapy of Myeloma Cancer Res., November 1, 2005; 65(21): 10041 - 10049. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. K. Stewart and R. Fonseca Prognostic and Therapeutic Significance of Myeloma Genetics and Gene Expression Profiling J. Clin. Oncol., September 10, 2005; 23(26): 6339 - 6344. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-Y. Huang, M. Yao, J.-L. Tang, W. Tsay, F.-Y. Lee, M.-C. Liu, C.-H. Wang, Y.-C. Chen, M.-C. Shen, and H.-F. Tien Clinical significance of cytogenetics and interphase fluorescence in situ hybridization analysis in newly diagnosed multiple myeloma in Taiwan Ann. Onc., September 1, 2005; 16(9): 1530 - 1538. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Moreaux, F. W. Cremer, T. Reme, M. Raab, K. Mahtouk, P. Kaukel, V. Pantesco, J. De Vos, E. Jourdan, A. Jauch, et al. The level of TACI gene expression in myeloma cells is associated with a signature of microenvironment dependence versus a plasmablastic signature Blood, August 1, 2005; 106(3): 1021 - 1030. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. van Rhee, S. M. Szmania, F. Zhan, S. K. Gupta, M. Pomtree, P. Lin, R. B. Batchu, A. Moreno, G. Spagnoli, J. Shaughnessy, et al. NY-ESO-1 is highly expressed in poor-prognosis multiple myeloma and induces spontaneous humoral and cellular immune responses Blood, May 15, 2005; 105(10): 3939 - 3944. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. M. Kuehl and P. L. Bergsagel Early Genetic Events Provide the Basis for a Clinical Classification of Multiple Myeloma Hematology, January 1, 2005; 2005(1): 346 - 352. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. C. Gutierrez, J. L. Garcia, J. M. Hernandez, E. Lumbreras, M. Castellanos, A. Rasillo, G. Mateo, J. M. Hernandez, S. Perez, A. Orfao, et al. Prognostic and biologic significance of chromosomal imbalances assessed by comparative genomic hybridization in multiple myeloma Blood, November 1, 2004; 104(9): 2661 - 2666. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Hideshima, P. L. Bergsagel, W. M. Kuehl, and K. C. Anderson Advances in biology of multiple myeloma: clinical applications Blood, August 1, 2004; 104(3): 607 - 618. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Murashige, Y. Kishi, W. J. Chng, P. Musto, and M. Attal Tandem Bone Marrow Transplantation in Multiple Myeloma N. Engl. J. Med., April 1, 2004; 350(14): 1466 - 1467. [Full Text] [PDF]
|
|
|
|
|
|
R. Fonseca, B. Barlogie, R. Bataille, C. Bastard, P. L. Bergsagel, M. Chesi, F. E. Davies, J. Drach, P. R. Greipp, I. R. Kirsch, et al. Genetics and Cytogenetics of Multiple Myeloma: A Workshop Report Cancer Res., February 15, 2004; 64(4): 1546 - 1558. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-L. Harousseau, J. Shaughnessy Jr., and P. Richardson Multiple Myeloma Hematology, January 1, 2004; 2004(1): 237 - 256. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Shaughnessy Jr Myeloma is on the move Blood, January 1, 2004; 103(1): 9 - 10. [Full Text] [PDF]
|
|
|
|
|
|
B. Barlogie, J. Shaughnessy, G. Tricot, J. Jacobson, M. Zangari, E. Anaissie, R. Walker, and J. Crowley Treatment of multiple myeloma Blood, January 1, 2004; 103(1): 20 - 32. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Tian, F. Zhan, R. Walker, E. Rasmussen, Y. Ma, B. Barlogie, and J. D. Shaughnessy Jr. The Role of the Wnt-Signaling Antagonist DKK1 in the Development of Osteolytic Lesions in Multiple Myeloma N. Engl. J. Med., December 25, 2003; 349(26): 2483 - 2494. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Shaughnessy Jr Primer on Medical Genomics Part IX: Scientific and Clinical Applications of DNA Microarrays--Multiple Myeloma as a Disease Model Mayo Clin. Proc., September 1, 2003; 78(9): 1098 - 1109. [Abstract] [PDF]
|
|
|
|
|
|
S. Barille-Nion, B. Barlogie, R. Bataille, P. L. Bergsagel, J. Epstein, R. G. Fenton, J. Jacobson, W. M. Kuehl, J. Shaughnessy, and G. Tricot Advances in Biology and Therapy of Multiple Myeloma Hematology, January 1, 2003; 2003(1): 248 - 278. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2003 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
2 values greater than 3.84 (P < .05) or
with "present" (P) detection in more than half of each
sample group were retained. To compare gene expression levels, the
nonparametric Wilcoxon rank sum (WRS) test was used to compare 2 groups
with the use of Signal. The cutoff was at least a P value
less than .001. SAM relies upon the microarray probe set
signal values (ie, mean of the signal intensity differences between the
20 matched and mismatched probes arrayed for each gene). Selecting the
SAM threshold with the lowest false-discovery rate (FDR)
(below 0.01) as a tool for exclusion of any false-positives generated
in the 
2 mg/dL) were associated
with inferior OS. Given the potential clinical implications of
CR and second autotransplantation, both CAs and SPFs were
re-examined in the context of time-dependent parameters. Results
indicated superior OS among patients achieving CR promptly and
whose relapse occurred late. When considered in the context of
SPFs, a CRP level of at least 4 mg/L was the only additional variable
that adversely affected both EFS and OS.
13) in multiple myeloma: an Eastern Cooperative Oncology Group study.
Cancer Res.
2002;62:715-720