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Prepublished online as a Blood First Edition Paper on June 7, 2002; DOI 10.1182/blood-2001-12-0297.
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Academic Unit of Haematology and Oncology,
University of Leeds, United Kingdom; Department of Haematology, Hull
Royal Infirmary, United Kingdom; and Department of Immunology,
University of Birmingham, United Kingdom.
Conventional monitoring strategies for myeloma are not sufficiently
sensitive to identify patients likely to benefit from further therapy
immediately after transplantation. We have used a sensitive flow
cytometry assay that quantitates normal and neoplastic plasma cells to
monitor the bone marrow of 45 patients undergoing high-dose
chemotherapy. Neoplastic plasma cells were detectable at 3 months after
transplantation in 42% of patients. Once detected, neoplastic cell
levels increased steadily until clinical progression: these patients
had a significantly shorter progression-free survival (PFS)
(median, 20 months) than those with no detectable disease (median,
longer than 35 months; P = .003). Neoplastic plasma cells were detectable in 27% (9 of 33) of immunofixation-negative
complete-remission patients. These patients had a significantly shorter
PFS than immunofixation-negative patients with no detectable neoplastic plasma cells (P = .04). Normal plasma cells were present
in 89% of patients immediately after transplantation, but were not
sustained in most cases. Patients with only normal phenotype plasma
cells present at 3 months after transplantation and also at second
assessment had a low risk of disease progression. Patients with
neoplastic plasma cells present at 3 months after transplantation, or
with only normal plasma cells present at first assessment and only neoplastic plasma cells at second assessment, had a significantly higher risk of early disease progression (P < .0001)
with a 5-year survival of 54% for the high-risk group, compared with
100% in the low-risk group (P = .036). Analysis of
normal and neoplastic plasma cell levels is more sensitive than
immunofixation and can identify which patients may benefit from
additional treatment strategies at an early stage after transplantation.
(Blood. 2002;100:3095-3100) Many patients who receive high-dose therapy
(HDT) for myeloma achieve a complete remission by conventional
criteria, with a minority achieving a molecular remission. However,
with current therapy, all patients eventually relapse as a consequence
of residual disease. To develop effective maintenance strategies, aimed
at prolonging the residual disease states, it is important to be able
to monitor the behavior of residual neoplastic plasma cells. In
addition to monitoring the malignant cells, it has also been suggested that recovery of normal immunoglobulin levels may be associated with improved outcome.1 Monitoring the recovery of normal plasma cells may therefore offer an additional approach to
predicting the outcome of autologous transplantation.
Current approaches to measurement of residual disease levels are
based on morphological assessment of bone marrow biopsies, analysis of
the paraprotein levels, or polymerase chain reaction (PCR)
analysis of the immunoglobulin heavy chain variable-diversity-joining (VDJ) region. Complete remission (CR) is currently defined as the absence of the original monoclonal paraprotein in serum and urine
by immunofixation as well as fewer than 5% plasma cells in the bone
marrow.2 Using these criteria, a number of studies have
shown that patients who achieve a complete remission have an improved
progression-free, and possibly also overall, survival compared with
partial responders or nonresponders.3-5 However, the
difference in survival is insufficient to justify using remission status defined by conventional criteria as a means for adjusting treatment. PCR strategies using primers specific to the neoplastic VDJ
region result in sensitivities of up to 1 in 106 cells.
However, such approaches are not quantitative and are labor-intensive,
and only 60% to 70% of patients have an amplifiable VDJ
region.6 Therefore, these strategies are difficult to
apply in a clinical setting, and it is not clear whether they improve the prediction of outcome after transplantation.7-9
An optimal assay for monitoring residual disease would be robust and
universally applicable, and could quantitate low levels of neoplastic
plasma cells. We have developed a flow cytometric technique for
identifying plasma cells with a sensitivity of 0.01%. The assay can
distinguish neoplastic plasma cells from their normal counterparts on
the basis of their CD19 and CD56 expression, even if both cell types
are present within the same sample.10,11 We have applied
this technique to bone marrow aspirates from a series of patients
undergoing autologous transplantation in order to determine whether the
levels of malignant and normal plasma cells predict outcome after
high-dose therapy.
Patients
Flow cytometry
The gating strategy is optimized to exclude contaminating events,
particularly B progenitors, which are common in samples from patients
immediately after transplantation, as well as apoptotic cells and
cellular debris. Analysis of CD38 versus CD138 expression (Figure
1Ai) provides the best separation of
plasma cells from other leukocytes, but is also subject to
contamination, with cells binding antibodies nonspecifically. This can
be detected on the CD38 versus CD45 plot (Figure 1Aiii) to the right of
the plasma cell population. Thus, an initial region (R1) is
set around cells expressing a high level of CD38 and CD138 (Figure
1Ai), and a second region (R2) set on the light scatter of gated
CD38+CD138+ cells (Figure 1Aii). A
third region (R3) was set around the cells satisfying both R1 and R2
for CD38 and CD45 expression (Figure 1Aiii). Regions R2 and R3 are then
optimized until events falling within both of these regions are all
CD138+ and CD3
Horizontal quadrant markers are set according to the CD3 control
for analysis of CD138 and CD19 expression. CD56 expression is weak on
normal plasma cells, and the marker is set higher than control (at 100 as standard) as this provides a better discrimination between normal
and neoplastic cells. The expression of CD19-PE and CD56-PE is then
used to distinguish between normal and neoplastic plasma cells. The
former are consistently CD19+CD56dim whereas
the latter are CD19 Dilute nonrepresentative aspirate samples are a significant problem in all minimal residual disease studies. This assay allows the identification of such samples in most cases. Those containing fewer than 0.01% normal or neoplastic plasma cells were always unrepresentative of the trephine biopsy appearance and were not included in the study. In this series of patients, unsuitable aspirates were received in approximately 6% (3 of 48) of cases. Marrow aspirate samples containing both neoplastic and normal plasma cells were always representative, as normal CD138+ plasma cells are found only in bone marrow, not in peripheral blood.10 All patients with disease on the trephine biopsy had neoplastic plasma cells detectable by flow cytometry, although the degree of infiltration was underestimated in a minority of cases. Fluorescent immunoglobulin heavy chain gene PCR analysis using consensus primers High molecular weight DNA was obtained from separated leukocytes by proteinase K digestion, phenol/chloroform extraction, and cold ethanol precipitation. DNA was amplified with a 5' FITC-labeled primer to a consensus region of the J heavy chain (JH) gene, and a primer to a consensus framework 3 (Fr3) region, or a mixture of primers to consensus framework 1 (Fr1) regions on each of the 6 VH gene families, as reported previously.6 Electrophoresis and analysis was performed by means of an Applied Biosystems (Foster City, CA) automated DNA sequencer. Electrophoretograms were produced from the fluorescence intensity data, representing the size and relative amount of each PCR product as a peak on a histogram. This PCR assay will detect neoplastic plasma cells at the level of 1 in 105 leukocytes if no other B cells are present. If B cells are present, which is the case in most patient samples, the assay will identify a population that represents more than 2% of total amplifiable B cells, equating to a sensitivity of 1 in 103 to 1 in 104 total leukocytes.13
Sensitivity of flow cytometry assay: comparison with consensus-primer immunoglobulin heavy chain-PCR We have previously demonstrated that fluorescent consensus-primer immunoglobulin heavy chain (IgH)-PCR has a comparable sensitivity for the detection of residual disease to immunofixation.3 To determine whether flow cytometric assessment would be more applicable, we compared the flow assay with consensus-primer IgH-PCR analysis. Twenty-five patients had amplifiable DNA from presentation marrow samples, of which 16 of 25 (64%) had an amplifiable IgH rearrangement. This is consistent with previous studies demonstrating an amplifiable rearrangement in up to 80% of patients.6,14 The flow assay detected neoplastic plasma cells at presentation in all patients included in this study, and we have previously demonstrated in a series of more than 500 patients that the assay will detect neoplastic plasma cells in more than 98% of cases.15Thirty-three follow-up samples were available from patients with an amplifiable IgH rearrangement. Neoplastic plasma cells were detected by flow cytometry in all PCR-positive samples (n = 10) and also in 16 of 23 PCR-negative samples. In PCR-negative samples, neoplastic plasma cell levels were below 0.2% of total leukocytes (median, 0.06%), consistent with the limits of sensitivity of the PCR assay in patient samples.13 The results indicate that flow cytometric analysis is applicable to a greater proportion of patients than IgH-PCR in general, and also has a greater sensitivity for detection of residual neoplastic cells than consensus-primer IgH-PCR. Comparison of conventional monitoring with flow cytometric analysis In this group of patients, 22% (10 of 45) achieved an immunofixation-negative complete remission, with the remaining 78% (35 of 45) achieving a partial response to induction therapy with C-VAMP. High-dose melphalan increased the complete remission rate to 73% (33 of 45), with 27% (12 of 45) remaining immunofixation positive. Neoplastic plasma cells were detectable at 3 months after transplantation in 27% (9 of 33) of the complete remission patients, and in 92% (11 of 12) of partial remission patients. To determine the reproducibility of the technique, 34 representative samples were reanalyzed retrospectively in a blinded fashion. Differences were noted in only 2 of 34 samples; in 1 case the difference was due to operator error on prospective analysis. In the other case, neoplastic plasma cells were present at a level close to the limit of detection of the flow assay, and the sample was prospectively reported as showing a normal plasma cell profile, but having evidence of residual disease on retrospective analysis. The clinical features suggest that the retrospective analysis was more accurate, as the patient remained immunofixation positive. However, to avoid potential bias, the results reported in this paper are from prospective analysis. This retrospective analysis demonstrates that the assay has good reproducibility, but reanalysis of borderline samples using larger numbers of cells may be beneficial in future studies.For patients achieving a complete remission after transplantation, the median time to achieve a negative immunofixation was 2.9 months after transplantation, with 12% (4 of 33) taking longer than 6 months to show undetectable levels of paraprotein. To assess whether neoplastic plasma cell levels showed the same kinetics, sequential samples were assessed in a cohort of 12 patients with neoplastic plasma cells detectable at 3 months after transplantation. A median of 2 further samples were analyzed (range, 1-7) with a median follow-up of 15 months from transplantation. In 11 of 12 patients, the levels of neoplastic plasma cells increased steadily; for 1 patient, the level of neoplastic plasma cells was stable (ie, within 0.05% of previous samples) for 17 months and then increased until clinical relapse occurred at 38 months. Thus, once neoplastic plasma cells are detected, the levels increase until overt clinical progression. These data suggest that analysis of neoplastic plasma cells is more sensitive than immunofixation in the majority of cases, and can be performed at a single time point, as once neoplastic cells are detected they do not decrease in level. Use of the flow cytometric assay improves prediction of outcome compared with standard criteria In this series of patients, attainment of an immunofixation-negative complete remission was associated with improved progression-free survival, but this only became apparent at 20 months after transplantation (Figure 2).
Patients with detectable paraprotein by immunofixation had a median progression-free survival of 21.5 months (95% confidence interval, 20-23 months), whereas only 12 of 33 immunofixation-negative patients have progressed with a median 30-month follow up (P = .002, log-rank test). Overall survival at 5 years was 77% for the complete responders compared with 52% for the partial responders, but this did not reach statistical significance (P = .16, log-rank test). When the presence or absence of neoplastic plasma cells was used to
define response, a similar pattern was seen, although there was
slightly better separation between the 2 arms in the first year after
transplantation compared with conventional monitoring (Figure
3).
Neoplastic plasma cells were detectable in the bone marrow of 42% of patients (19 of 45) at 3 months after autologous transplantation. Patients with detectable neoplastic plasma cells had a median progression-free survival of 20 months (95% confidence interval, 18-23 montha), whereas only 9 of 26 in the group of patients with no neoplastic plasma cells have progressed with a median 34.5 months follow-up (P = .0034, log-rank test). Survival at 5 years was 64% for the group with neoplastic plasma cells compared with 76% for those with no detectable neoplastic cells, although again this did not reach significance (P = .28, log-rank test). Neoplastic plasma cells were detectable in 9 of 33 (27%) of the
immunofixation-negative (IF Univariate and multivariate analysis of outcome was performed for a
range of criteria shown in Table 1. The
detection of paraprotein by immunofixation was not significant in
multivariate analysis; however, the detection of neoplastic plasma
cells at 3 months remained significant. This demonstrates the increased sensitivity of the flow cytometric assay for detection of residual disease. In patients with detectable neoplastic plasma cells, approximately half become immunofixation negative but show an outcome
identical to patients who remain immunofixation positive. Presentation
Normal plasma cells are present in the bone marrow of most patients at 3 months after transplantation. If this level is sustained for 6 months, patients have a significantly better prognosis At 3 months after transplantation, normal plasma cells were detectable in 89% (40 of 45) of patients, and normal CD19+ B-lymphocytes were present in all patients. Previous studies have suggested that the recovery of normal immunoglobulin is a powerful prognostic factor, but the proportion of patients recovering normal levels is much lower. Analysis of sequential samples in 25 patients demonstrated that 16 of 25 patients had normal plasma cells at second assessment (6 to 12 months after transplantation), and all 16 of these patients recovered normal immunoglobulin levels. These patients had a much better prognosis: only 2 of 16 have progressed at 40 and 49 months after transplantation, respectively, with a median follow-up of 39 months. However, the median time to recovery of normal immunoglobulin levels was 6 months, and ranged from 3 to 15 months. Therefore, recovery of normal immunoglobulin levels is not a suitable parameter for identifying patients requiring further upfront therapy. Of the 9 patients who had only neoplastic plasma cells at second assessment, all had continued immuneparesis. The outcome of the latter group was similar to the poor outcome of patients with detectable neoplastic plasma cells at 3 months, showing a median progression-free survival of 16 months from transplantation (range, 7-39 months).The data suggest that it is possible to identify 2 groups of patients
with very different outcomes, on the basis of the detection of normal
and neoplastic plasma cells at first and second assessment after
transplantation. In a cohort of 35 patients, we defined a high-risk
group (n = 23) as those who have neoplastic plasma cells present at 3 months after transplantation or who have only normal plasma cells
present at first assessment and only neoplastic plasma cells at second
assessment. The low-risk group had only normal phenotype plasma cells
present at 3 months after transplantation and also had normal plasma
cells present at second assessment (n = 12). Figure
4 demonstrates a highly significant
difference in progression-free survival between these groups
(P < .0001). In addition, there is also a significant
difference in overall survival (P = .036), with a 5-year
survival of 100% for the low-risk group, compared with 54% in the
high-risk group.
In this study, we have assessed the clinical relevance of minimal disease monitoring in patients with multiple myeloma after high-dose chemotherapy using conventional criteria, as well as flow cytometric and PCR approaches. Flow cytometric analysis has not been widely used as a method for residual disease analysis in multiple myeloma, but has been previously shown to be extremely effective in chronic lymphocytic leukemia.13 It has been demonstrated that a unique neoplastic plasma cell phenotype is identifiable in more than 98% of patients, and that the technique can be extremely sensitive.15 We have demonstrated in this study that a relatively simple flow cytometric technique can identify a group of patients with particularly good prognosis, and a second group with a much poorer progression-free and overall survival. More recently identified neoplastic markers may allow further
improvement of flow cytometric disease monitoring in
myeloma.16 However, during this study, we have identified
several factors that are essential for residual disease assessment.
Factors that affect any residual disease assay are the use of good
quality "first-pull" marrow aspirate and the analysis of sufficient
leukocytes (preferably 100 000 to 500 000). Particularly relevant to
flow cytometric analysis is the exclusion of B-progenitor cells, which have a phenotype similar to that of normal plasma cells
(CD38++CD19+CD56 Numerous PCR strategies have been applied for residual disease monitoring in myeloma, with some showing an improved outcome for those achieving an minimal residual disease-negative (MRD-negative) status,8 and some showing no difference.9 A major drawback to PCR analysis is the relatively low number of patients with an amplifiable IgH rearrangement using consensus primers, as a result of a high degree of somatic hypermutation in the neoplastic cells.6 Analysis using consensus primer PCR is relatively insensitive and provides no additional information to what is provided by immunofixation.3 Allele-specific oligonucleotide (ASO)-PCR approaches are more sensitive, but also more labor-intensive and cannot differentiate between myeloma plasma cells and clonally related B cells. This is critical since some investigators have detected B cells clonally related to the myeloma plasma cells after transplantation, yet their presence does not predict early relapse, possibly because these cells may not be proliferative.17,18 This may explain why most patients remain ASO-PCR positive after autologous transplantation and why monitoring does not always predict outcome in this setting.7 As in previous studies, we have demonstrated that patients achieving a complete remission have an improved progression-free survival compared with partial remission patients.4 However, this difference becomes apparent only after prolonged follow-up, and many CR patients show early relapse. Furthermore, it may take up to 9 months after transplantation for immunofixation to become negative. Therefore, conventional criteria cannot be used to identify patients who might benefit from additional therapy in the early stages after high-dose therapy. Flow cytometric analysis of normal and neoplastic plasma cells provides a much more powerful prediction of outcome in this cohort and can be assessed at fixed time points as the result does not depend on variable immunoglobulin half-life. It has been suggested that neoplastic plasma cell levels might remain stable over time in some patients after transplantation.19 However, in this study, neoplastic plasma cell levels always increased with time until disease progression, and their identification at an early stage predicts a poor outcome. Patients who had only normal plasma cells at first assessment but only neoplastic plasma cells at second assessment also had a poor outcome. This distinct group of patients who respond well initially but relapse quickly has previously been identified in studies of conventional chemotherapy.20 Patients with only normal plasma cells at first assessment and who maintain normal plasma cells at second assessment are nearly all in remission with a median follow-up from transplantation of approximately 3 years. These patients also show recovery of normal immunoglobulin levels that have previously been identified as a good predictor of outcome.1 It seems probable that this group of patients will not benefit from additional therapy immediately after transplantation but should be monitored regularly for residual disease on maintenance therapy. In contrast, patients with detectable neoplastic plasma cells at 3 or 6 months after transplantation should be considered for further treatment, such as further high-dose therapy, low-intensity conditioning allogeneic transplantation, or experimental therapeutic strategies.
The majority of patients investigated in this study were treated in the Medical Research Council Myeloma VII trial (Adult Leukaemia Working Party Chairman Prof A. K. Burnett).
Submitted December 21, 2001; accepted May 21, 2002.
Prepublished online as Blood First Edition Paper, June 7, 2002; DOI 10.1182/blood-2001-12-0297.
Supported by The Leukaemia Research Fund, United Kingdom; and Yorkshire Cancer Research, United Kingdom.
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: Andy C. Rawstron, HMDS, Academic Unit of Haematology and Oncology, Algernon Firth Bldg, University of Leeds, Leeds LS1 3EX, United Kingdom; e-mail: andy.rawstron{at}hmds.org.uk.
1.
Zent CS, Wilson CS, Tricot G, et al.
Oligoclonal protein bands and Ig isotype switching in multiple myeloma treated with high-dose therapy and hematopoietic cell transplantation.
Blood.
1998;91:3518-3523 2. Blade J, Samson D, Reece D, et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol. 1998;102:1115-1123[CrossRef][Medline] [Order article via Infotrieve]. 3. Davies FE, Forsyth PD, Rawstron AC, et al. The impact of attaining a minimal disease state after high-dose melphalan and autologous transplantation for multiple myeloma. Br J Haematol. 2001;112:814-819[CrossRef][Medline] [Order article via Infotrieve]. 4. Lahuerta JJ, Martinez-Lopez J, Serna JD, et al. Remission status defined by immunofixation vs. electrophoresis after autologous transplantation has a major impact on the outcome of multiple myeloma patients. Br J Haematol. 2000;109:438-446[CrossRef][Medline] [Order article via Infotrieve]. 5. Alexanian R, Weber D, Giralt S, et al. Impact of complete remission with intensive therapy in patients with responsive multiple myeloma. Bone Marrow Transplant. 2001;27:1037-1043[CrossRef][Medline] [Order article via Infotrieve].
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Owen RG, Johnson RJ, Rawstron AC, et al.
Assessment of IgH PCR strategies in multiple myeloma.
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Corradini P, Voena C, Tarella C, et al.
Molecular and clinical remissions in multiple myeloma: role of autologous and allogeneic transplantation of hematopoietic cells.
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Martinelli G, Terragna C, Zamagni E, et al.
Molecular remission after allogeneic or autologous transplantation of hematopoietic stem cells for multiple myeloma.
J Clin Oncol.
2000;18:2273-2281 9. Swedin A, Lenhoff S, Olofsson T, Thuresson B, Westin J. Clinical utility of immunoglobulin heavy chain gene rearrangement identification for tumour cell detection in multiple myeloma. Br J Haematol. 1998;103:1145-1151[Medline] [Order article via Infotrieve]. 10. Rawstron AC, Owen RG, Davies FE, et al. Circulating plasma cells in multiple myeloma: characterization and correlation with disease stage. Br J Haematol. 1997;97:46-55[CrossRef][Medline] [Order article via Infotrieve].
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The interleukin-6 receptor alpha-chain (CD126) is expressed by neoplastic but not normal plasma cells.
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Harada H, Kawano MM, Huang N, et al.
Phenotypic difference of normal plasma cells from mature myeloma cells.
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Rawstron AC, Kennedy B, Evans PA, et al.
Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize therapy.
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2001;98:29-35 14. Aubin J, Davi F, Nguyen-Salomon F, et al. Description of a novel FR1 IgH PCR strategy and its comparison with three other strategies for the detection of clonality in B cell malignancies. Leukemia. 1995;9:471-479[Medline] [Order article via Infotrieve].
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Ashcroft J, Rawstron AC, Owen RG, Morgan GJ.
Phenotyping in myeloma: identification of a rare CD19+56 16. Almeida J, Orfao A, Ocqueteau M, et al. High-sensitive immunophenotyping and DNA ploidy studies for the investigation of minimal residual disease in multiple myeloma. Br J Haematol. 1999;107:121-131[CrossRef][Medline] [Order article via Infotrieve].
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Yaccoby S, Epstein J.
The proliferative potential of myeloma plasma cells manifest in the SCID-hu host.
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1999;94:3576-3582 18. Rottenburger C, Kiel K, Bosing T, et al. Clonotypic CD20+ and CD19+ B cells in peripheral blood of patients with multiple myeloma post high-dose therapy and peripheral blood stem cell transplantation. Br J Haematol. 1999;106:545-552[CrossRef][Medline] [Order article via Infotrieve]. 19. Almeida JJ, Mateo GG, Orfao AA, et al. An immunophenotypic pattern characteristic of MGUS is achieved following autologous stem cell transplant in multiple myeloma [abstract]. Blood. 2000;96:421a. 20. Oivanen TM. Plateau phase in multiple myeloma: an analysis of long-term follow-up of 432 patients. Finnish Leukaemia Group. Br J Haematol. 1996;92:834-839[CrossRef][Medline] [Order article via Infotrieve].
© 2002 by The American Society of Hematology.
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  B. Paiva, M.-B. Vidriales, G. Mateo, J. J. Perez, M. A. Montalban, A. Sureda, L. Montejano, N. C. Gutierrez, A. Garcia de Coca, N. de las Heras, et al. The persistence of immunophenotypically normal residual bone marrow plasma cells at diagnosis identifies a good prognostic subgroup of symptomatic multiple myeloma patients Blood, November 12, 2009; 114(20): 4369 - 4372. [Abstract] [Full Text] [PDF]
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 R. Gupta, A. Bhaskar, L. Kumar, A. Sharma, and P. Jain Flow Cytometric Immunophenotyping and Minimal Residual Disease Analysis in Multiple Myeloma Am J Clin Pathol, November 1, 2009; 132(5): 728 - 732. [Abstract] [Full Text] [PDF]
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A. M. Harrington, P. Hari, and S. H. Kroft Utility of CD56 Immunohistochemical Studies in Follow-up of Plasma Cell Myeloma Am J Clin Pathol, July 1, 2009; 132(1): 60 - 66. [Abstract] [Full Text] [PDF]
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B. Paiva, M.-B. Vidriales, J. Cervero, G. Mateo, J. J. Perez, M. A. Montalban, A. Sureda, L. Montejano, N. C. Gutierrez, A. G. de Coca, et al. Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation Blood, November 15, 2008; 112(10): 4017 - 4023. [Abstract] [Full Text] [PDF]
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 G. Mateo, M. A. Montalban, M.-B. Vidriales, J. J. Lahuerta, M. V. Mateos, N. Gutierrez, L. Rosinol, L. Montejano, J. Blade, R. Martinez, et al. Prognostic Value of Immunophenotyping in Multiple Myeloma: A Study by the PETHEMA/GEM Cooperative Study Groups on Patients Uniformly Treated With High-Dose Therapy J. Clin. Oncol., June 1, 2008; 26(16): 2737 - 2744. [Abstract] [Full Text] [PDF]
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 A. C. Rawstron, A. Orfao, M. Beksac, L. Bezdickova, R. A. Brooimans, H. Bumbea, K. Dalva, G. Fuhler, J. Gratama, D. Hose, et al. Report of the European Myeloma Network on multiparametric flow cytometry in multiple myeloma and related disorders Haematologica, March 1, 2008; 93(3): 431 - 438. [Abstract] [Full Text] [PDF]
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M. H. A. Rayes, A. C. Rawstron, G. J. Morgan, and F. E. Davies The bone marrow microenvironment influences the differential chemokine receptor expression of normal and neoplastic plasma cells Blood, June 15, 2005; 105(12): 4895 - 4896. [Full Text] [PDF]
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F. E. Davies, A. M. Dring, C. Li, A. C. Rawstron, M. A. Shammas, S. M. O'Connor, J. A.L. Fenton, T. Hideshima, D. Chauhan, I. T. Tai, et al. Insights into the multistep transformation of MGUS to myeloma using microarray expression analysis Blood, December 15, 2003; 102(13): 4504 - 4511. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
2 microglobulin (
.
subgroup [abstract].
Blood.
2000;96:156a.