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Clinical Investigations |
13) in Multiple Myeloma
Mayo Clinic Department of Hematology and Internal Medicine, Department of Laboratory Medicine and Pathology, Rochester, Minnesota 55905 [R. F., G. W. D., R. J. B., S. A. V. W., K. J. H., S. V. R., N. E. K., P. R. G.]; Eastern Cooperative Oncology Group Statistical Center, Dana Farber Cancer Institute, Boston Massachusetts 02115 [D. H., E. A. B.]; Virginia Piper Cancer Institute, Minneapolis, Minnesota 55407 [M. M. O.]; and University of Minnesota, Minneapolis, Minnesota 55455 [B. V. N.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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13) have been associated with an unfavorable prognosis in patients with multiple myeloma (MM). The significance of this has been unresolved because of diverse methods of detection and heterogeneous groups of patients. We conducted a study of 13 in patients entered into the Eastern Cooperative Oncology Group trial E9486/E9487. Patients with newly diagnosed MM (median follow-up of survivors >100 months) were studied for 13, using bone marrow samples obtained at study enrollment. We used interphase fluorescence in situ hybridization with the probes LSI13 (Rb)/D13S319 with simultaneous immunofluorescence detection of bone marrow plasma cells (PCs). We detected 13 in 176 of 325 (54%) evaluable patients. Patients with 13 were more likely to have a serum monoclonal protein at a concentration 
1 g/dl (22 versus 13%; P = 0.04), light-chain-only MM (19.3 versus 10.8%; P = 0.04), 
light chain (42 versus 28%; P = 0.027), stage III (56 versus 42%; P = 0.014), and be female (60 versus 50%; P = 0.087). The PC labeling index and 13 correlated (P = 0.03). Patients with 13 were less likely to respond to treatment (74 versus 63%; P = 0.041) and had a significantly shorter median overall survival (34.9 versus 51 months; P = 0.021). The association of 13 and survival remained an independent prognostic variable in a regression model. Among patients with 13, those receiving IFN had a worse overall survival that those not receiving the medication (P = 0.03). The presence of 13 is an important and independent adverse prognostic factor in newly diagnosed MM and is associated with specific biological features. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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13), especially 13q- and monosomy, are common in MM3
PCs, as detected by karyotype analysis (15–20%; Refs. 1, 2, 3
), multicolor metaphase FISH (4
, 5)
, and comparative genomic hybridization (6
, 7)
. Deletions of 13q14 have been detected in 30–50% of MM patient samples by interphase FISH studies (8, 9, 10, 11, 12)
, with the majority of 13 representing monosomy (13
, 14)
.
Detection of 13 by conventional karyotype analysis has been documented as a powerful adverse prognostic factor in MM patients treated with high-dose chemotherapy and stem cell support (15
, 16) . However, in MM there is a strong association between obtaining informative abnormal metaphases and a high PCLI and extent of bone marrow involvement (17)
. Recent observations have proposed that 13 abnormalities detected by interphase FISH are also associated with an adverse prognosis in MM (8
, 9
, 12)
. To further establish the prognostic significance of the abnormality, 13 needs to be studied in a larger cohort of patients treated uniformly and who have all relevant prognostic variables assessed, including the most important one, PCLI. We therefore decided to test the prognostic, predictive, and biological significance of 13 in newly diagnosed MM patients entered into ECOG clinical trial E9486 and the associated correlative laboratory trial E9487 (18)
. This latter set of clinical and laboratory studies in MM is ideal because this same cohort of patients has been tested for relevant prognostic factors in MM (18
, 19)
. In addition, the clinical trial contains mature survival data since the study was closed to accrual in 1992.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2. The study regimens and response criteria are described in detail by Oken et al. (18)
. Patients randomized to the IFN-2-containing regimen initiated this medication on day 22 of their third cycle of treatment (approximately day 64). Patients entered on the cyclophosphamide arm had to be <70 years of age. A total of 561 patients were enrolled in the E9487 laboratory correlative study. The median survival for all patients was 40.5 months, with a 5-year survival rate of 29%. The median follow-up for survivors was 108 months at the time of publication (range, 86–127 months). A total of 351 patients were included in this study for our analysis (Table 1)
. This subset of patients was chosen based on sample availability (frozen slides) and not for any specific patient features. This subset cohort did not appear to differ from the larger cohort of patients entered into the E9487 study (data not shown) when tested for all relevant biological and prognostic markers.
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Bone Marrow Samples.
Institutional Review Board approval was obtained according to the guidelines for research with human subjects. Bone marrow aspirates were obtained at the time of study entry and submitted to the MM cell bank at the Mayo Clinic. The aspirates were enriched for mononuclear cells by the Ficoll gradient centrifugation method. Cytospin slides were made and stored at -70°C for future use. For this interphase FISH study, slides were thawed and subjected to immunofluorescence detection of the cIg light chain with clone-specific, 7-amino-4-methylcoumarin-3-acetic acid-labeled antibodies (
or ) as described previously (20)
.
Probes.
To test for 13, we used the LSI 13 (Rb) and D13S319 probes from Vysis, Inc. These probes have been extensively tested in normal cells and hybridize to the 13q14-13q14.3 region (Ref. 14
; Fig. 1
). A normal pattern was considered to be that of two pairs of closely associated signals. An abnormal pattern was that of loss of signal(s) from one of the pair of probes.
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13 had the genetic lesions detected in >50% of clonal PCs (median, 97%), this "cutoff" criterion for positive 13 proved not to be critical for the analysis. Patients were considered evaluable if at least 100 PCs could be scored. Two independent scorers read blindly and independently each slide, thus counting a total of 200 cells per sample.
MVD.
Bone marrow angiogenesis was assessed using immunostaining for CD34 as previously described by us (21
, 22)
. The average number of vessels in three hot spots counted at x400 magnification was used to determine the MVD. We also categorized patients as having low, intermediate, and high angiogenesis as described previously (21
, 22)
.
Statistical Analysis.
Descriptive statistics were used to characterize patients in the study. Fisher’s exact test (23)
was used to test differences among levels of categorical variables between patients with normal versus 13 scores. For continuous variables, the Wilcoxon rank-sum test (24)
was used to test for differences between normal and 13 patients. The distributions for overall survival and progression-free survival were estimated using the method of Kaplan and Meier (25)
. The log-rank test was used to test for differences in survival between groups (26)
. Median overall survival and median progression-free survival times were obtained from the estimated survival curves, and 95% confidence intervals for these estimated times were based on the sign test (27)
. To identify possibly important prognostic factors, Cox proportional hazards models (28)
were used. To examine the simultaneous association of several potentially important prognostic factors on survival, we used a stepwise regression technique with Cox proportional hazards models. Factors were retained in the model if they were statistically significant at P 0.05.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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13, 325 were evaluable (92%) and 176 were found to have 13 (54%). The biological features of patients with successful FISH analysis were not different from those of patients not evaluable (data not shown). The only feature common to patients not evaluable for 13 was that they were more likely to be nonevaluable for other FISH assays, thus indicating that failure likely was related to technical aspects of the bone marrow sample storage (data not shown). The median number of PCs with loss of hybridization signals was 97% (range, 13–100%), and 161 patients had >50% abnormal PCs. In 172 cases (98%), there was simultaneous loss of LSI 13 (Rb) and D13S319 signals, and only 4 cases had variant deletions. There was a high degree of agreement between the findings of genetic lesions in the PCs provided by the two independent scorers (r2 = 0.99).
Clinical Features of Patients
Patient Features.
The clinical and laboratory features of patients according to the presence or absence of 13 are shown in Tables 1
1 and 2
. There were no significant differences in the prevalence of 13 according to gender, ethnicity, or age, but some trends emerged. For MM patients younger than age 50, 65% had 13 compared with 52% in others (P = 0.1), and among patients younger than age 40, 71% had 13 compared with 53.7% in others (P = 0.46). Women appeared to be more likely to have 13 (60%) than men (50%; P = 0.087). African-American patients (n = 39) were slightly less likely to have 13 compared with Caucasians (n = 270; 44 versus 54%; P = 0.2). There was also a positive association between 13 and stage III MM. Of patients with 13, 56% were stage III compared with 42% of patients with normal results (P = 0.014).
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13 were more likely to have a serum monoclonal protein concentration 1 g/dl (22 versus 13%; P = 0.04), light-chain-only MM (19.3 versus 10.8%; P = 0.04), and were more likely to have light chains of the type (42 versus 28%; P = 0.027). There was no correlation between plasmablastic morphology and 13 (19
, 29) . Plasmacytomas were observed in similar proportions between patients with and without 13. There appeared to be no difference in the bone marrow PC percentage between patients with and without the abnormality. Similarly there was no correlation between 13 and CRP and sIL-6R.
PCLI and ß2-M.
The PC proliferative activity, as determined by the PCLI, was higher among patients with 13 (Wilcoxon P = 0.03; Fig. 2
). Serum levels of ß2-M appeared to be similar between both groups of patients (Wilcoxon P > 0.2). We performed a multiple logistic regression analysis with 13 as the response variable and the laboratory features that were found significant in univariate analysis [serum M component present/absent (<1 g/dl), light-chain-only disease, PCLI, and ß2-M] as the predictors. The only variable that remained marginally significant in predicting 13 was PCLI (P = 0.08).
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13. Patients were equally likely to have low-, intermediate-, or high-grade angiogenesis irrespective of 13 status. Similarly, the median MVD was not significantly different between patients with or without 13 (P > 0.2).
Response and Survival Analysis
Among patients evaluable for response (n = 319), those with 13 had a lower likelihood of an objective response than those without the abnormality (63 versus 74% respectively; P = 0.04; Table 3
). There was no difference in the likelihood of patients achieving a complete response according to the presence or absence of 13 (12 versus 16% respectively; P = 0.4).
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13 also had a significantly worse overall survival (Fig. 3)
and progression free survival (Fig. 4)
. The median survival of patients with 13 was 34.9 months compared with 51 months among patients without the abnormality (P = 0.021, log-rank). The median progression-free survival times were 24.1 versus 32.5 months for patients with and without 13, respectively (P = 0.028, log-rank). Postprogression survival was not different between patients with and without 13 [11.5 (n = 123) versus 19.6 months (n = 109); P = 0.11, log-rank]. There was no significant difference in the rate of infection between patients with and without 13 in the first 6 or 12 months after study enrollment.
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13 (n = 176), the administration of IFN-2 was associated with a worse outcome based on an inferior overall survival (28.6 versus 39.6 months; P = 0.03, log-rank; Fig. 5
). This association was not caused by an imbalance in stage distribution because among patients with 13, the stage distribution was roughly equivalent for those patients on the IFN-2 arm and those not on the IFN-2 arm. There were no significant survival differences for IFN-2 administration, versus not, for patients without 13 (P > 0.2, log-rank).
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13 and other known prognostic variables, using stepwise fitting techniques for the proportional hazards regression. The prognostic factors in our "candidate set" included 13, percentage of bone marrow PCs, ß2-M, PCLI, sIL-6R, CRP, creatinine, albumin, hemoglobin, heavy-chain isotype, serum light chain, and Durie-Salmon stage (I and II versus III). To be placed or remain in the model, a factor had to be significant at the 0.05 level. The above continuous variables were made categorical by use of published cutoff points to divide the patients into two categories. The cutoff points were as follows: bone marrow PCs > 30%; ß2-M > 2.7 mg/dl; PCLI 
1%; sIL-6R 270 ng/ml; CRP 2 mg/dl; creatinine 2 mg/dl; albumin > 3 g/dl; and hemoglobin > 10 g/dl. We had data on all of these factors for 295 of the 325 evaluable patients. Forward, backward, and stepwise variable selection procedures all produced the same final regression model: 13, percentage of bone marrow PCs, ß2-M, PCLI, and creatinine. The relative risk for these variables ranges from 1.34 (13) to 1.74 (creatinine), showing that all were associated with substantially higher risk of death. Details about this model are shown in Table 4
. Using the same proportional hazards regression model to assess for progression-free survival, we found that 13 was not statistically significant (P = 0.08).
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13 with Other Prognostic Variables13 and an elevated PCLI to other patients, using two PCLI cutoff points: 0.8% (n = 70), and 1% (n = 57). The median survival of these two subset of patients was significantly shorter compared with the other patients: 26.6 versus 46.5 months when we used the 0.8% cutoff (P = 0.002) and 24.1 versus 46.7 months when we used the 1% cutoff. (P < 0.001).
Likewise, we have also used the same prognostic model proposed by Facon et al. (12)
and have found that it accurately discerns three groups of patients: those with 13 and a ß2-M >2.5 mg/dl; those with one of the two risk factors; and patients with neither. The median survival times for these three groups were 33.2, 45, and 61 months, respectively (P < 0.0001).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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13 detected by cIg-FISH for the biological classification and prognostication of MM patients. We found the abnormality in 54% of patients, and it was associated with a shorter overall survival, lower likelihood of response, advancing stages of the disease, and higher PCLI. Deletions of 13 have emerged as an important prognostic factor for the evaluation of newly diagnosed MM patients.
The prevalence of 13 in this cohort of patients is slightly higher than that reported by some authors (8, 9, 10
, 30)
but not others (31)
. The set of probes used for this study is standard and comparable to what has been used by many others. These probes localize to the most common area of deletion of chromosome 13 in MM. Although some investigators have reported a higher incidence of 13 (31)
, most data support a prevalence of 
50% (8, 9, 10
, 30) . Using a larger number of probes would be of no use because we and others have shown that among patients with 13 in MM, 85% of these cases represent monosomy (8, 9, 10
, 30)
. The combination of cytomorphological identification of PCs and cytoplasmic staining allows us to postulate that, at present, evidence supports the prevalence we report. We have also concluded that when the abnormality is present, it is usually detected in a nonheterogeneous manner, i.e., in the majority of the clonal PCs (14)
. This has been confirmed by others and further supports (11
, 13)
that 13 is an important lesion in the clonal PC, which is favored with clonal evolution.
The present study also allows for independent evaluation of 13 as a prognostic factor in MM without the confounding effects of detection of 13 by karyotype analysis (16)
. In addition, the availability of the most important prognostic markers in MM, PCLI and ß2-M, allows us to compare 13 with factors reflective of tumor burden and proliferation. The results of our study are further strengthened by the extended follow-up clinical information, superior to that of any other reported study (30)
and with the resulting minimal censoring (8%). The adverse effect on prognosis is most evident soon after the time of diagnosis, so that even when the 5-year survival was clearly superior among patients without 13, there were no perceived differences at 10 years. Thus, the presence of 13 by FISH is not universally associated with a dismal outcome.
Our study supports a lessened contribution of 13 to an adverse outcome when detected by cIg-FISH compared with 13 detected by karyotype analysis (15
, 16)
. We have previously shown correlation between a high PCLI and the detection of abnormal metaphases by karyotype analysis (17)
. Given the common occurrence of 13 in MM (50%), we speculate that detection of 13 by karyotype analysis in fact is an adverse factor that represents a combination of several prognostic variables, such as 13 and a high PCLI (1%). In our series, the proportion of patients with this combination of factors (18%) is similar to the proportion of patients with 13 detected by karyotype analysis (15–20%; Refs. 2
, 15
, 32
, 33
). Preliminary studies done at our institution have revealed that the group of patients with an elevated PCLI and 13 by cIg-FISH have a significant overlap with patients with 13 by karyotype.4
Although MM is frequently aneuploid, chromosome 13 is rarely trisomic, even in cases with informative metaphases (1 , 2 , 34) . In a recent study by the University of Arkansas, the authors did not report frequent occurrence of chromosome 13 trisomy (35) . In that particular study (which used multicolor metaphase FISH in patients with informative karyotypes), the authors found chromosome 13 monosomy in 54% of cases, exactly the number of cases we found in our study. We rarely (0.5%) detected patients with three signals in the PCs, which is indicative of trisomy. In other studies using comparative genomic hybridization, gains in chromosome 13 are not frequent; thus it is unlikely that a meaningful proportion of cases with MM have gains of chromosome 13 (6 , 7) . Although a rare patient may have lost one chromosome 13 while having a trisomy, as detected by karyotype, this is likely rare and of unknown clinical significance. Interphase FISH may miss a very small percentage of patients with a trisomic chromosome 13 and only two copies of chromosome 13, but it is still much more sensitive for the detection of chromosome 13 abnormalities than karyotype analysis. These facts argue that a good validated set of interphase FISH probes, such as those used in this study, are appropriate for the study of chromosome 13 monosomy in MM. We have recently found that all cases with chromosome 13 monosomy or deletion reported by karyotype analysis can also be detected by interphase FISH.4
We have documented the adverse prognostic significance of 13 in MM as suggested previously by karyotype analysis and FISH, but the reason for the apparent linkage is unclear. Although the inferior response to treatment could be postulated as causative of the lower overall survival, it could be just another indicator of the aggressive nature of the clone. We did not find a higher rate of complete response according to 13 as reported by Facon et al. (12)
for patients treated by high-dose chemotherapy. It is possible that 13 represents a surrogate marker of other important cytogenetic abnormalities, with which 13 is strongly associated [e.g., t(4;14)(p16.3;q32); Ref. 36
], and that these abnormalities are the ones that confer the negative prognostic importance to the detection of 13. It is intriguing that the median survival of patients with 13 in our study (treated with standard-dose chemotherapy) was comparable to that of patients with 13 treated with high-dose chemotherapy in the study by Facon et al. (12)
despite those patients being treated with a more intensive regimen (34.9 versus 27 months). In contrast, the survival of patients without 13 in our series (51 months) appears to be shorter than that reported by Facon et al. (12)
for patients treated with high-dose therapy (65 months), suggesting that the net benefit of high-dose chemotherapy is greater in patients without evidence of 13.
Increased PC proliferation has also been suggested as the mechanistic explanation for the observed adverse outcome in MM and 13. In the study by Zojer et al. (9)
, the authors found a higher proliferative rate among patients (n = 5) with 13 than those without the abnormality (n = 5). Although we observed a higher proportion of patients with high PCLI among those with 13, the majority of patients had overlapping PCLI values. Other mechanisms, such as a lower apoptotic rate (37)
or increased angiogenic stimuli, may also explain the worsened outcome of these patients (38)
. However, unlike the recent observation by Schreiber et al. (38)
in newly diagnosed and untreated MM patients, we were unable to correlate 13 and increased bone marrow neoangiogenesis in our cohort of patients.
This study, like the one by Facon et al. (12)
, has provided evidence of biological differences between patients with and without 13. There is a significant association between 13 and light-chain type as well as MM with a serum monoclonal protein concentration 1 g/dl. Similarly, the abnormality would appear to be more common among women and younger patients. We have been unable to confirm the association of 13 with elevated lactate dehydrogenase, lower hemoglobin level, older age, and the tendency for a higher ß2-M (12)
. However, although some of the perceived biological differences were of statistical significance, none were extreme.
Our finding that IFN-2 administration resulted in shorter overall survival among MM patients with 13 needs to be prospectively tested in a larger cohort of MM patients, and the mechanisms behind this observation need to be better elucidated. IFN-2 may act as a survival factor and protect MM cell lines from corticosteroid-induced apoptosis (39, 40, 41)
. Indeed, recent data suggest that IFN-2 may result in up-regulation of Mcl-1, acting as an antiapoptotic molecule (42)
. Anecdotal experience suggests that IFN-2 may be deleterious to some MM patients, whereas there is a subset who benefit from the latter type of intervention (43)
. In support of this, Jelinek et al. (44)
have shown heterogeneous patterns of response of human MM cell lines to IFN administration, with IFN-2 acting as a growth factor for the human MM cell line KAS-6/1.
Determination of 13 status should be incorporated in all future clinical trials for accurate prognostication of patients. One of the challenges for the future will be to incorporate all relevant prognostic variables in a model that can address them simultaneously. Preliminary observations by our group and others suggest specific clustering of abnormalities. For example, we and others have found that the t(4;14)(p16.3;q32) in MM is strongly associated with 13 (11
, 36
, 45
, 46)
. This same association has been suggested for t(14;16)(q32;q23), but we have been unable to confirm it.4
To conclusively establish the prognostic importance of 13 in MM, it will be important to dissect the specific contribution of each cytogenetic abnormality (i.e., patients with 13 but none of these other abnormalities).
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FOOTNOTES |
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1 R. F. and S. V. R. are Leukemia and Lymphoma Society Translational Research Awardees. This work was supported in part by Public Health Service Grant R01 CA83724-01 (to R. F.) and Grant P01 CA62242 (to P. R. G.) from the National Cancer Institute. R. F. and P. R. G. are also supported by the Mayo Foundation and by the CI-5 Cancer Research Fund-Lilly Clinical Investigator Award of the Damon Runyon-Walter Winchell Foundation. P. R. G. and N. E. K. are supported by ECOG Grant CA21115-25C from the National Cancer Institute. 
2 To whom requests for reprints should be addressed, at Division of Hematology and Internal Medicine, Stabile 6-22, Rochester, MN 55905. Phone: (507) 266-2162; Fax: (507) 266-9277; E-mail: fonseca.rafael{at}mayo.edu
3 The abbreviations used are: MM, multiple myeloma; PC, plasma cell; FISH, fluorescence in situ hybridization; PCLI, plasma cell labeling index; ECOG, Eastern Cooperative Oncology Group; VBMCP, vincristine, carmustine, melphalan, cyclophosphamide, and prednisone; ß2-M, ß2-microglobulin; CRP, C-reactive protein; sIL-6R, soluble, interleukin-6 receptor; cIg, cytoplasmic immunoglobulin; MVD, microvessel density.
4 R. Fonseca, Monosomy 13 in myeloma can always be detected by interphase FISH, manuscript in preparation.
Received 7/20/01. Accepted 12/ 3/01.
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REFERENCES |
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13) in both multiple myeloma (MM) and MGUS. Blood, 98: 1271-1272, 2001. protects myeloma cell lines from dexamethasone-induced apoptosis. Leukemia, 13: 473-480, 1999.[Medline]
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