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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 7 (April 1), 1998:
pp. 2501-2507
Plasmablastic Morphology An Independent Prognostic Factor With
Clinical and Laboratory Correlates: Eastern Cooperative Oncology
Group (ECOG) Myeloma Trial E9486 Report by the ECOG Myeloma Laboratory
Group
By
Philip R. Greipp,
Traci Leong,
John M. Bennett,
Jean P. Gaillard,
Bernard Klein,
James A. Stewart,
Martin M. Oken,
Neil E. Kay,
Brian Van Ness, and
Robert A. Kyle
From the Mayo Clinic, Rochester, MN; Dana Farber Cancer Institute,
Boston, MA; the University of Rochester, Rochester, NY; the University
of Nantes, Nantes, France; the University of Wisconsin, Madison;
Virginia Piper Cancer Institute, Minneapolis, MN; the University of
Kentucky, Lexington; and the University of Minnesota, Minneapolis.
 |
ABSTRACT |
We studied the prognostic significance of plasmablastic (PB)
multiple myeloma (MM) in Eastern Cooperative Oncology Group Phase III
trial E9486. Two reviewers independently reviewed 453 cases. They
agreed on 37 PB (8.2%) cases and 416 non-PB cases, achieving an 85%
concordance (P < .0001). These PB cases had significantly lower hemoglobin and serum albumin levels, higher calcium and  2-microglobuin levels, and higher percentage BM plasma cells (PC) by
immunofluorescence. They had higher bone marrow PC labeling indices,
higher serum soluble interleukin-6 receptor (sIL-6R) levels, and a
higher probability of ras mutations. Three treatment regimens
were used: vincristine, bis-chloro-ethyl nitrosourea (BCNU) melphalan,
cyclophosphamide, and prednisone (VBMCP) alone; VBMCP with
added cyclophosphamide (HiCy); or recombinant interferon  2 (rIFN2). Although the numbers are low, patients
with PB had a significantly lower response rate versus non-PB MM when
treated with VBMCP (treated, 47.1% v nontreated, 66.5%
[P = .015]). Patients with nonresponding PB had a
significantly higher progression rate than non-PB cases (30.6%
v 11.8% [P < .0001]), especially with VBMCP
alone (35.3% v 15.8% [P = .002]), and with
added HiCy (37.5% v 9.8% [P < .0001]), but not
with added rIFN2. Event-free and overall survival of PB MM was
shorter (median years, 1.1 v 2.7 and 1.9 v 3.7, respectively [P < .0001 for both]). In multivariate analysis, PB classification was also highly prognostic. There is no
survival difference between the patients who were classified as PB by
both reviewers versus patients classified as PB by only one reviewer.
We conclude that PB MM is a discrete entity associated with more
aggressive disease and shortened survival. Tumor cell ras
mutations and increased sIL-6R may contribute to a higher proliferation
rate and reduced survival. There were significant improvements in
response and progression with the addition of HiCy and rIFN2 to
VBMCP, but the numbers were small and improved survival could not be
shown.
| |
INTRODUCTION |
MULTIPLE MYELOMA (MM) is a neoplastic
disease of bone marrow (BM) plasma cells (PC) causing lytic bone
lesions, anemia, renal insufficiency, and hypercalcemia. Survival
varies from just a few months to 10 or more years. The plasma cell
labeling index (PCLI) directly measures increased myeloma cell
proliferation and has been shown to be a reliable prognostic
factor.1 This increased PC may be accompanied by
morphological differences. Earlier observations showed that
morphological classification of MM identifies plasmablastic (PB)
features, and can distinguish patients with a poor
prognosis.1-9 PB features have been associated with other
aspects suggesting aggressive disease, including high PCLI,3 high serum lactic dehydrogenase
level,10-11 VLA-5 negativity among immature PCs,
proliferation of myeloma cells in response to interleukin-6
(IL-6),12 and establishment of in vitro myeloma cell
lines.13 We investigated morphological and biological
features of patients with MM who were entering a large clinical trial
to improve understanding of the prognostic impact of PB morphological changes in MM.
Definitions of PB MM differ, making it difficult to know if one can
compare studies and apply PB classification in practice or in clinical
trials. We described a simplified classification system to identify PB
MM from BM aspirates.3 There have been three subsequent
studies by other groups using this classification system. One study
confirmed that this classification can identify a poor prognosis MM
subset.10 A second study by the same investigators showed
no long-term survivors in patients with PB MM.14 A third study showed that PB morphology did not represent an unfavorable category unless patients with the immature morphology were also included.15 To further develop this classification system,
we tested it in a cooperative group clinical trial, with slides
submitted at entry for study by clinical investigators and examination
by two independent pathology reviewers.
We report the results of marrow aspirate slide review in 453 newly
diagnosed MM cases entering Eastern Cooperative Oncology Group (ECOG)
trial E9486 who also had studies on companion Myeloma Laboratory Group
study E9487. We focused on survival analysis of PB cases and
identification of clinical and biological correlates, including PCLI,
ras mutations, and soluble IL-6 receptor (sIL-6R) level.16 We addressed the following questions: What are the clinical and biological correlates of PB MM? Is PB MM an adverse prognostic factor and does it add to prognostic information provided by
existing prognostic factors? We also explored whether adverse effects
of PB morphology might be offset by high-dose cyclophosphamide (HiCy)
or recombinant human interferon 2 (rIFN2) added to the VBMCP
regimen used in this trial.
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MATERIALS AND METHODS |
Patient selection.
We analyzed morphological data from untreated symptomatic patients with
MM entered and eligible for ECOG clinical trial E9486 and companion
laboratory study E9487 over a 5-year period ending in May 1992 and
followed through July 1996. Of 653 patients entered on E9486, 561 were
also entered on E9487. Of 538 eligible for both studies, 453 had
morphological data. Of the 85 cases without morphological data, 31 were
coded as not readable, 53 were coded as pending at the time of
analysis, and 1 case was missing.
Patient demographics are described in Table
1. Staging was performed according to a
modification of the Durie Salmon criteria.17 Patients were
randomly assigned to receive either regimen A, VBMCP; regimen B, VBMCP + HiCy; or regimen C, VBMCP + rIFN2. Patients entered on the HiCy
arm had to be less than 70 years of age. The study required submission
of Wright-stained BM aspirate slides at the time of study entry. The
453 eligible patients had BM aspirates classified by two morphologists
(J.M.B. and P.R.G.). Ancillary laboratory sample submission was
initiated and was made mandatory after the first 18 months of accrual.
Studies performed on samples sent to the Mayo Clinic Myeloma Tumor
Biology Laboratory (Rochester, MN) included the PCLI, percentage PCs by
immunofluorescence, serum C-reactive protein (CRP), and 2-microglobulin levels (2M). sIL-6R levels were performed at the
laboratory of B.K. Other standard laboratory variables
included BM examination; metastatic bone survey; serum and urine
protein electrophoresis and immunoelectrophoresis; and measurement of
serum calcium, creatinine, albumin, and hemoglobin levels at the member
institutions. Patients fulfilled ECOG diagnostic criteria for MM and
had to have symptomatic, progressive disease before protocol entry.
Patients with monoclonal gammopathy of undetermined significance (MGUS)
and smoldering MM were excluded from this study.
Morphological classification system.
The two independent reviewers examined BM air-dried smears prepared
with the Wright-Giemsa stain or Wright stain. Before the study began,
an example slide set and classification criteria were sent to J.M.B.
for study. The two reviewers then met after 6 months to compare
interpretation of a test set of 50 cases entering the study. We did not
change the original classification of either reviewer on those or
subsequent cases.
PB MM is a morphologic subset of myeloma defined on the Wright-stained
BM aspirate slide as containing  2%
PB.3 Briefly, areas of the aspirate slide
are identified for evaluation. There must be a good spread of cells and
high quality of staining, sufficient to identify critical features of
the plasma cells, including nuclear chromatin pattern, nuclear size,
nucleolar size, and cytoplasmic distribution. Each reviewer identifies
500 plasma cells and enumerates the percent PB. When the percent PB is
very close to 2%, the reviewer counts another 500 plasma cells. PB are
characterized as follows: the nucleus must have a fine reticular
chromatin pattern (no or minimal chromatin clumping); the nucleus must
be large (estimated to be greater than 10 µm), or it must have a
large nucleolus (estimated to be greater than 2 µm); and the
cytoplasm must have no or very little hof region, and less abundant
cytoplasm (less than one-half of the nuclear area). In our previous
study, 2% or more plasmablasts among the plasma cell population
constituted a significant predictor of survival. Because of
morphological heterogeneity, the reviewers thoroughly reviewed the
entire area of a well-spread slide before concluding whether the case
did or did not exhibit PB morphology in any area of the slide. Figure
1 shows a representative example of PB MM.
Several examples of typical plasmablasts can be seen.
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| Fig 1.
Shown in panels A, B and C, are PB and immature (IMM)
plasma cells. PB have fine reticular chromatin, scant cytoplasm (less than half the area of the nucleus), little or no hof, and either a
large nucleus (>10 µm), or a large nucleolus (>2 µm). IMM
plasma cells have the same nuclear features, but more abundant
cytoplasm and usually a more prominent hof region.
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After independent examination of the stained aspirate slides by each
reviewer, and without knowledge of the other's interpretation, results
were coded on submission forms and sent to the ECOG statistical office
for data entry, storage, and analysis. Data were compared for agreement
between the reviewers. To avoid bias or dominant influence by one
investigator and to ensure the group of patients reported here
represented PB MM, we classified the myeloma as PB only if both
reviewers agreed.
PCLI.
PCLI were determined by immunofluorescence microscopy using a
previously described technique.18 We used
fluorescein-conjugated antiserum to  and  light chain on
alcohol-fixed cytospin slides of BM mononuclear cells to identify
clonal PCs and an antibody to 2-bromodeoxyuridine (BrdU) followed by a
rhodamine-conjugated anti-mouse immunoglobulin (Ig) antisera to
identify cells in S-phase of the cell cycle. A : ratio greater
than 4:1 or less than 0.5:1 was considered abnormal. Cells stained with
the light chain of the nondominant isotype were considered to be
nonclonal and were not included in the labeling index determination.
The labeling index was measured by counting the percentage of
BrdU-labeled cells among 500 PCs on a slide stained with the anti-
or anti- reagent identifying the dominant PC isotype.
Other assays.
CRP measurement was performed using immunoephelometry (Beckman
Instruments, Inc, Brea, CA). The normal value is <0.8
mg/dL. The 2M measurement was performed using a microparticle enzyme immunoassay (MEIA Technology) on Abbott Diagnostics
Instrumentation (Abbott Laboratories, Abbott Park, IL). The normal
value is  2.7 µg/mL. These analyses were performed on fresh serum
stored no longer than 2 weeks at 4°C. sIL-6R levels were performed by
radioimmunoassay in the laboratory of B.K. in Nantes,
France.16 Normal value is 300 ng/mL. Ras
mutations were determined by polymerase chain reaction amplification of
codons 12, 13, and 61 of the N- and K-ras genes followed by
single-stranded conformation polymorphism,19 oligonucleotide dot blot hybridization,20 direct DNA
sequencing, or restriction fragment polymorphisms.21
Response to treatment.
Response to treatment was defined according to ECOG criteria. Objective
response required a reduction in serum and urine M-protein to 50% of
pretreatment level. If no measurable serum M-protein was present
(<1.0 g/dL), a reduction in urine M-protein to 10% of pretreatment
level was required. Protein requirements for response had to be
verified on two consecutive determinations separated by at least 2 weeks. Patients with measurable soft tissue plasmacytomas had to have a
50% reduction in the sum of the products of the cross diameters. Serum
and urine M-protein levels were measured by electrophoresis and not
quantitative Ig levels, except where the serum M-spike was considered
unreliable by the study chair. For objective response criteria to be
met, there had to be no new bone lesions, no increase in lytic lesions,
and no recurrence or persistence of hypercalcemia. Patients with
nonsecretory MM and no soft tissue plasmacytomas were considered to
have an objective response if the BM PC percentage decreased to less
than 50% of pretreatment values. No response constituted the group who
failed to meet objective response criteria outlined above. Patients who met two or more of the following criteria were considered to have relapse or progression: (1) an increase in serum M-protein to 50%
above the lowest remission level or a rise of 2.0 g/dL; (2) an increase
in 24-hour urine M-protein to 50% above the lowest remission value or
an increase of 2 g/24 hours of M-protein and an M-protein of greater
than 250 mg/24 hours; (3) an increase in soft tissue plasmacytomas by
50% as measured by the sum of the products of the cross diameters of
each measurable lesion; (4) the definitive appearance of a new lytic
bone lesion or an increase in size of existing lesions by 50%.
Progression by skeletal disease alone required discussion with the
study chair before removing the patient from study; and (5) a 50%
increase in serum or urine M-protein plus one of the following:
hypercalcemia 12 mg/dL, decrease in hemoglobin 2.0 g/dL to <11
g/dL in men or <10 g/dL in women in absence of evidence of
myelodysplasia or other cause of anemia, increase in BM PCs by 50% or
generalized bone pain. Patients who progressed without previous
objective response were considered separately.
Statistical analysis.
Concordance was analyzed using the statistic. Distribution of
patient characteristics among the PB and non-PB groups was tested for
balance using Fisher's Exact test.22 Distribution of
laboratory characteristics across the PB and non-PB groups were tested
using the Wilcoxon test.23 Event free survival (EFS) was
computed from the time of study registration to progression, relapse,
or death. Overall survival (OS) was computed from the time of study
registration to date of death or date last known to be alive. Survival
curves were estimated by using the method of Kaplan and
Meier24 with differences assessed by the log rank test.25 All P values were two sided, unless
otherwise noted. The Cox model was used for multivariate
analyses.26 To assess the joint effect of individual
prognostic factors with PB morphology, all the significant factors were
considered simultaneously to develop a multiple proportional hazards
regression model. To arrive at a parsimonious model, a backward
elimination procedure was adopted. At each step of the model fitting,
the Wald test was used to eliminate variables until all the remaining
variables had a P value of .05.
| |
RESULTS |
Of 453 BM aspirates reviewed, 37 (8.2%) were classified as PB by both
reviewers, and 416 were classified as non-PB by at least one of the
reviewers. In 386 of 453 cases there was agreement between J.M.B. and
P.R.G. as to whether cases were PB or not for an overall concordance of
85%. We used the statistic to evaluate the agreement between the
reviewers. This statistic corrects for agreement caused by chance. If
the agreement is high, then there is the possibility that there is
usefulness in the morphological classification. The range of is
from  1 (high disagreement) to 1 (high agreement). The statistic
is .440 and the one-sided P value testing whether the value of
= 0 (random agreement) versus > 0 is significant at P < .0001.
Clinical and laboratory characteristics.
A total of 627 patients were registered and eligible from
ECOG Trial E9486/E9487. Of the 627, 453 had morphological and
laboratory data. Table 1 shows the patient characteristics at on-study
grouped by PB status. The 37 PB cases had similar distribution of age, sex, and Ig characteristics as did non-PB cases. PB cases had a higher
incidence of serum creatinine (2 mg/dL), calcium (12 mg/dL), BM
PCLI (1%), and hemoglobin (<10 g/dL; P .001). A higher proportion of PB myeloma cases were stage III (70.3% v 54.1%; P = .06). Table 2presents median values of laboratory characteristics for PB cases at
on-study. High values of 2M, PCLI, serum calcium, and creatinine and
low values of albumin and hemoglobin are associated with PB morphology.
As seen in Table 2, PB cases had higher serum levels of the sIL-6R than
non-PB cases. PB cases also had a higher percentage of PCs measured
during the performance of the PCLI by immunofluorescence microscopy
(PCP-Imm, P = .004). Among 21 cases with >70% plasma
cells, 23% were called PB compared with 7.4% for 311 cases with
40% plasma cells. The %PC estimated from the bone marrow aspirate
from the referring institution failed to correlate with the showing of
PB myeloma.
Analysis for ras mutations disclosed single or multiple point
mutations in 39% of patients entering the study.27 As seen in Table 2, the probability of a ras mutation, given PB MM, was greater than the probability of a ras mutation, given non-PB
morphology (P = .013).28
Response to treatment and progression.
Two-thirds (66.7%) of 627 patients who were eligible E9486 cases
achieved an objective response. Similarly, 302 of the 442 patients
(68.3%) evaluable for response and with morphological data who were
registered and eligible to both E9486 and E9487 achieved an objective
response. Twenty-one of the 36 PB cases (58.3%) evaluable for response
had objective responses compared with 281 of 406 (69.2%) for non-PB
cases (Table 3). Although the response
rates for PB cases were lower, they were not significantly different.
For nonresponders, there was a significant difference in the incidence
of progression 30.6% for the PB cases compared with 11.8% for the
non-PB cases (P < .0001). Of nonresponders who progressed,
most (51%) did so by the first year and almost all (80%) progressed
before the second year.
Response to treatment regimens.
Table 4 presents the categories of response by each
treatment: (A) VBMCP, (B) VBMCP + HiCy, and (C) VBMCP + rIFN2. When the three treatment arms were analyzed for response separately, there
were significant differences in objective response for PB versus non-PB
cases for VBMCP, but not for VBMCP + HiCy or for VBMCP + rIFN2. The
difference in response rate for PB cases treated with VBMCP alone
versus non-PB cases was statistically significant (47.1% v
66.5%, P = .015). The objective response rate for PB MM for
each of the regimens was incrementally higher: VBMCP alone, 47.1%;
VBMCP + HiCy, 62.5%; and VBMCP + rIFN2, 72.7%. However, because
the number of patients with PB MM is small, the differences in response
rates for PB cases across the three arms did not reach statistical
significance.
Disease progression after treatment regimens.
With VBMCP alone there was a higher incidence of progression in
non-responders, 35.3% in PB MM compared with 15.8% in non-PB MM
(P = .002). Similarly, in cases treated with VBMCP + HiCy
there was a higher incidence of progression in nonresponders in PB MM of 37.5% compared with 9.8% in non-PB MM (P < .0001). In
cases treated with VBMCP + rIFN2 there was no difference in the
incidence of progression in nonresponders. Although, in patients with
nonresponding PB the incidence of progression was lower using the VBMCP + rIFN2 regimen (18.2%) than with VBMCP alone (35.3%) or VBMCP + HiCy (37.5%) (Table 4). This difference was not statistically
significant.
EFS.
As shown in Fig 2, the PB cases have a significantly
shorter EFS than the non-PB cases, with medians of 1.1 and 2.7 years (P < .0001). Comparing the EFS by treatment regimen, there
were no significant differences in survival, perhaps because of the small numbers of PB cases in each arm.
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| Fig 2.
EFS differences for patients with PB morphology () and
non-PB morphology (---) are depicted. Note the greater number of events (relapse and progression) in the PB group, particularly in the first
year. Median EFS of patients with PB morphology and non-PB morphology
was 1.1 versus 2.7 years (P < .0001).
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Survival.
Overall survival by PB morphology is shown in Fig 3. PB
cases had significantly shorter survival (P < .0001), with
a median of 1.9 years, compared with 3.7 years for non-PB cases. The
survival of the PB cases was not different when divided by treatment
regimen. There is no survival difference between the patients who were classified as PB by both reviewers versus patients who were classified as PB by only one reviewer.
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| Fig 3.
OS differences for patients with PB morphology () and
non-PB morphology (---) are depicted. Note the greater number of deaths in the PB group, particularly in the first 2 years. Median survival of
patients with PB morphology and non-PB morphology was 1.9 versus 3.7 years (P < .0001).
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Univariate and multivariate analysis for prognostic factors.
PB morphology, in univariate analysis, imparts a poor prognosis
compared with non-PB cases (P < .0001), as seen in Fig 3. Table 5 presents the univariate survival analysis of
selected patient characteristics. The 2M, PCLI, sIL-6R, creatinine,
albumin, hemoglobin, and calcium are all significant at P .001. CRP, level of urine Bence Jones protein, stage, and sex are
significant at P < .05. In multivariate analysis (Table
6), the following variables are reported in order of
risk ratio, as jointly and independently associated with poor survival:
PB morphology, high PCLI, serum sIL-6R, 2M, CRP, creatinine, and PC
percentage by immunofluorescence.
| |
DISCUSSION |
Despite numerous publications on PB myeloma, there is a lack of clear
understanding of the definition and significance of this entity. In a
previous single-institution study of 100 patients with newly diagnosed
MM seen at the Mayo Clinic, we showed the prognostic significance of PB
morphology.3 Verifications by another
group10,14 and positive studies at our
institution1,29 justify looking at PB MM in a cooperative
group. Advantages include uniform treatment and standard follow-up;
uniformly collected laboratory data for correlative study; accurate
data showing response, time of progression, and relapse
afforded by a rigorous review and consensus by the principal
investigator and data management team in the trial; and the large
number of cases afforded by a cooperative group study. An added
advantage is the integrated design of laboratory studies performed by
investigators from different institutions working collaboratively and
collectively as the ECOG Myeloma Laboratory Group. Out of this planned
collaboration and prospective banking of sera and cells came the study
of ras mutations and soluble IL-6 receptor analyses, correlated
with PB and its outcomestudies not possible in a single-institution
study.
In this series, we again confirmed that patients with PB features had
poorer survival than those with simply immature morphology by using the
classification method described in our previous
publication.3 The 85% concordance and the statistic of
.440 between two independent reviewers at separate institutions
represents good reproducibility. We believe this to be an important
step toward the development and acceptance of criteria for recognizing
PB MM as a separate morphologic entity.
The identification of PB MM is not an artifact, but it is a discrete
identifiable entity with distinguishing clinical and biological
characteristics. There is no apparent relationship of PB morphology to
ordinary clinical and laboratory features such as age or sex, presence
or absence of bone lesions, or type of M-protein in the serum or urine.
However, the fact that ras mutation carries with it a higher
frequency of PB morphology suggests that PB MM may be, in part, a
manifestation of an activating ras mutation that potentiates
the growth of myeloma cells. A full analysis of ras mutations
in E9486 including its relationship to PB morphology has been reported
separately.27
PB cases also have higher serum levels of soluble IL-6R, a soluble
cytokine receptor which can amplify myeloma cell proliferation in
response to IL-6. Other studies show that sIL-6R is an important step
in the pathogenesis of MM. There are increased levels detected in the
serum in MM, compared with MGUS,16 and sIL-6R may amplify plasmablast response to cytokines as suggested by Klein and
Bataille.30
PB cases tend to have more advanced and aggressive disease manifested
by more frequent anemia, renal insufficiency, hypercalcemia, a higher
PC percent by immunofluorescence, a higher PCLI and 2M, and a lower
albumin level. The prognostic significance of PB MM can be shown even
after one considers the status of these and other independent risk
factors such as sIL-6R and CRP. This observation of independence from
known prognostic factors shows that these factors do not adequately
explain the poor prognostic impact of PB morphology. Although not a
proven feature of PB MM, one can hypothesize that the aggressive
behavior of plasmablasts and PB MM may in part reflect an increased
IL-6 responsiveness associated with ras mutation. It will be
important to further study and understand the biological basis for the
poor prognosis associated with PB MM.
Treatment implications of PB MM suggested by this study are intriguing.
The higher incidence of progression in nonresponders has been suggested
previously.31 Although the numbers are small, there
appeared to be a higher response rate with added HiCy or rIFN2 and a
lower rate of progression in nonresponders treated with added rIFN2.
There was not a survival advantage for either regimen. Although in this
trial, combination chemotherapy using VBMCP with added rIFN2 or HiCy
did not improve survival, there may be subsets of patients who benefit
from this treatment. In trial E9486, the addition of rIFN2 during
induction seemed to prolong survival in patients over the age of 70 and
there was a trend toward longer survival in those with IgA myeloma. The potential of benefit for additional subgroups including those with PB
MM should be considered in the design and analysis of future trials of
rIFN2 in MM.
An intergroup cooperative group MM clinical trial including ECOG, the
Southwest Oncology Group, and Cancer and Leukemia Group B addresses the
role of peripheral stem cell transplant in MM. We are particularly
interested to see if peripheral stem cell transplant can improve
survival in the PB MM subset. Four reviewers at different institutions
will study BM aspirates to see whether patients with PB morphology are
more likely to benefit from early intensive therapy with peripheral
stem cell transplant.
In conclusion, PB MM represents a discrete entity in phase III trial
E9486/E9487. It is an independent prognostic factor predicting shorter
EFS and OS. A more frequently elevated level of PCLI, 2M, CRP, and
creatinine, and a lower albumin level characterize PB MM as a more
advanced and aggressive form of disease. Higher incidence of
ras mutations and of elevations of sIL-6R suggest potential
underlying mechanisms of aggressive behavior. Currently limited in use,
PB classification of MM is potentially useful in practice and in
clinical trials. Until more intensive therapy is definitively shown to
be beneficial, we cannot conclude that it is a better approach for
patients with PB MM.
| |
FOOTNOTES |
Submitted November 6, 1997;
accepted November 19, 1997.
Supported in part by Public Service Grants No. CA 13650, CA 23318, CA
21076, CA 15947, CA 20365, CA 11083, CA 21115, and CA 62242 from the
National Cancer Institute, National Institutes of Health, and the
Department of Health and Human Services. This study was conducted by
The Eastern Cooperative Oncology Group. Its contents are solely the
responsibility of the authors and do not necessarily represent the
official views of the National Cancer Institute.
Presented in part at the Meeting of the American Society of Hematology,
December 4-8, 1992, Anaheim, CA, and at the Meeting of the American
Society of Clinical Oncology, May 20-23, 1995, Los Angeles, CA.
Address reprint requests to Philip R. Greipp, MD, Division of
Hematology, Mayo Clinic, Hilton Room 920, 200 1st Ave SW, Rochester, MN
55905.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
We express our gratitude to Fran Silva for superb data management
assistance, Roxanne Tabery for excellent technical support, and
Kathleen Payne and Terrie Plank for fine secretarial support.
| |
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Abstract
Introduction
Abstract