Leukemia Research 23 (1999) 1133 – 1140

www.elsevier.com/locate/leukres

Mature plasma cells as indicator of better prognosis in multiple

myeloma. New methodology for the assessment of plasma cell
morphology
Jean E. Goasguen a,*, Marc Zandecki b, Claire Mathiot e, Jean-Marie Scheiff c,
Marie Bizet f, Béatrice Ly-Sunnaram a, Bernard Grosbois a, Matthieu Monconduit f,
Jean-Louis Michaux c, Thierry Facon d
a
Uni6ersite de Rennes, Hopital SUD, 16, Bld de Bulgarie, 35056 Rennes, France
b
Uni6ersity of Angers, Angers, France
c
Uni6ersity of Brussels, Brussels, Belgium
d
Uni6ersity of Lille, Lille, France
e
Uni6ersity of Paris, Institut Curie, IFM (Intergroup Francoplane du Myelome), Paris, France
f
Uni6ersity of Rouen, Rouen, France
Received 18 February 1999; accepted 7 June 1999

Abstract

The relationship between plasmablastic cells and outcome in multiple myeloma (MM) has been established for nearly 15 years.
But the assessment of these cells is not easy to perform and it allows the identification of only a small proportion of patients. We
investigated the plasma cell morphology using a progressive evaluation of consecutive criteria: nucleolus, chromatin and
nuclear-cellular ratio (N/C). The combination of these three items produces a subclassification where four cellular subtypes
identify 93% of the plasma cells, and these subtypes are related to the outcome. The interest of this methodology is to be based
on the mature plasma cells that are easier to identify than the plasmablastic cells. These new cell subtypes introduce a new
classification for patients: Group 1 includes patients with at least 66% mature plasma cells (P000). Both Group 2 and 3 have less
than 66% P000 and are separated by their degree of maturation (Proplasma I ] Proplasma II + plasmablastic). The distinction of
these three groups of patients is highly related to the prognosis (PB10 − 4). These results have been confirmed on a second group
of patients coming from a different institution. In conclusion, we propose a new methodology for the plasma cell evaluation in
MM, that is based on the morphological criteria and that has the advantage of identifying an intermediate (30%) subgroup of
patients with a prognostic significance. © 1999 Elsevier Science Ltd. All rights reserved.

Keywords: Multiple myeloma; Plasma cells; Morphology

1. Introduction an independent prognostic factor in multiple myeloma

Plasma cell morphology observed on bone marrow
sections or on films has been demonstrated [1 – 7] to be
Abbre6iations: BMT, Bone marrow transplantation; IFM, Inter
groupe Francophone du Myelome; MM, multiple myeloma; N/C,
nucleo-cellular ratio; P, plasma cell; PB, plasmablastic cell.

Illustration of plasma cell morphology as described in this paper
may be checked on the Web site of the first author at the following
address: http://www.med.univ-rennes1.fr/hemato.
* Corresponding author. Tel.: +33-2-99-26-71-52; fax: + 33-2-99-
26-71-16.
E-mail address: goasguen@univ-rennes1.fr (J.E. Goasguen)
(MM) for more than 15 years. Most studies are based
on the identification of plasmablastic cells (PB — at
least 2%) [3], these latter cases defining a subgroup of
patients representing 8–15% of all the cases of MM
[2,3]. This plasmablastic subgroup is related to a very
bad prognosis since the overall survivals are reported as
10 and 21 months, respectively. However, a prognostic
value was not demonstrated [3] for the more mature
cells were referred to as immature, intermediate, and
mature. These results have recently been confirmed [8]
but the main conclusion is that the recognition of PBs
may be very difficult, even when performed by experi-

0145-2126/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S 0 1 4 5 - 2 1 2 6 ( 9 9 ) 0 0 1 3 2 - 0
1134 J.E. Goasguen et al. / Leukemia Research 23 (1999) 1133–1140
enced morphologists, because the cell subset represents
only a very small number of cells (more or less than
2%) together with a small number of patients (8.7% in
the last report). Moreover, PBs do not reflect the
degree of maturation of the total proliferating popula-
tion and their assessment by immunological markers
such as CD38 or CD49e (integrin VLA5) may be
difficult [7].
Considering the long-term survivors in a large pop-
ulation of MM (1119 cases) in Japan [9], it was ob-
served that they were associated (P B 0.01) with the
presence of more mature plasma cells in the bone
marrow.
To have a better evaluation of all plasma cells,
including the more mature cells, we developed a new
methodology, and we applied it on two different
groups of patients. The first group originates from a
multicentric co-operative study (Universities of Ren-
nes, Angers, Lille, Paris, Rouen, Brussels). Five mor-
phologists reviewed bone marrow smears, partial
results with shorter follow-up have been reported
[11,12]. The second group is provided by a single
institution (University of Lille, France) and a single
observer (JG) performed the morphological analysis.
The aims of this investigation was to look for easy
and pertinent morphological criteria and to verify the
impact of the morphology analysis on the patient out-
come as predictive factor.
2. Materials and method
2.1. Patients
The evaluation of plasma cells was performed on
two different series of patients with multiple myeloma.
Study 1 included 92 cases from the MY90 protocol
(Intergroupe Francophone du Myelome — IFM,
France) dedicated to comparing interferon alpha and
prednisone associated with melphalan on continuous
versus discontinuous regimens as already published
[10]. The MY90 protocol included 230 patients from
1990 to 1996, and the 92 first available slides were
included for plasma cell morphology review. These 92
slides constituted a set that could circulate between
morphologists. Patients were considered as Group A
for all cases and Group B when restricted to respon-
ders and non-responders only.
Study 2 included 62 cases from a single institution
(University of Lille, France) for whom bone marrow
slides and clinical information were available. This
study was randomised to compare intensive (including
autologous bone marrow transplantation or high dose
melphalan without stem cell support) versus conven-
tional (according to standard protocol from IFM)
therapy in MM.
2.2. Method
All bone marrow smears were observed after May
Grunwald staining. Five qualified morphologists (JG,
CM, J-MS, MB, MZ) reviewed Study 1 slides. They
first had a multi-headed microscope preparation work-
ing party. After comparison and testing of the repro-
ducibility, they decided to apply the method described
below. A second study was launched to validate the
results on a different group of patients coming from a
single institution. A single investigator (JG) tested the
validity of the method between co-operative and single
studies respectively.
2.3. Morphology e6aluation method
2.3.1. Assessment of pertinent morphological criteria at
single cell le6el
The first part of the working parties was dedicated
to the search for the respective value of each morpho-
logic criteria and specially the reproducibility of their
evaluation. The following criteria were studied: size of
cytoplasm and N/C ratio; golgi zone (absent, present,
location); size of the nucleus and its location; aspect
of the chromatin (fine, coarse, intermediate); nucleolus
(size, prominent). Only three criteria appeared to be
reproducible (\ 85%) between the five observers and
these included: (i) nucleoli; (ii) blastic chromatin; and
(iii) N/C ratio] 0.6 as it is explained below.
2.3.1.1. Nucleoli. A nucleolus is usually defined by a
size of at least 2 mm and its evaluation is reproducible
only when the question concerns its presence (obvious
or not), and if the possible answers are only yes or
no. Consequently the first question is: ‘Is the nucleolus
present?’ and answers may be only: yes (1); or no (0).
2.3.1.2. Chromatin. There are many ways to evaluate
the aspect of the chromatin but to reach the best
reproducibility the question must concerns only the
blastic aspect. For this reason the question is: ‘Is the
chromatin with blastic aspect?’ and the answers may be
only: yes (1); or no (0).
2.3.1.3. N/C ratio. A large cytoplasm is more related
to differentiated plasma cell, and in contrast the plas-
mablastic cells are considered with a reduced propor-
tion of cytoplasm. To approach the degree of
maturation, we tested different values for the nuclear/
cellular ratio, and observed that N/C = 0.6 is a value
that can be assessed with reproducibility and confi-
dence after minimal training [13]. After training and
testing, we decided to work on N/C =0.6 and the
final question was: ‘Is the N/C ratio\ 0.6 ?’. The ex-
pected answers are: yes (1); or no (0).
 J.E. Goasguen et al. / Leukemia Research 23 (1999) 1133–1140
Fig. 1. Construction of algorithm for automatic subclassification of plasma cells in MM. The three questions are consecutives, and the answers
are yes (1) or no (0). Four subtypes represented 93% of the cells. These more frequent subtypes can be easily recognised by direct observation.
Since the three questions are consecutive, one cell can
be defined as ‘P111’ when the plasma cell (P) is defined
by ‘presence of nucleolus’, ‘presence of blastic chromatin’
and ‘N/C ratio\ 0.6 ’. This cell is very similar to the
description of a plasmablastic cell [3,8]. On the con-
trary, a cell defined by P000 is a mature plasma cell
(Marschalko cell) since there is no nucleolus (0), no
blastic chromatin (0), and no N/C \ 0.6 (0). This al-
gorithm is represented on Fig. 1 where finally eight
subtypes are defined. These subtypes are represented in
a synoptic table (Fig. 2) and illustrated in Fig. 3 to
explain their significance.
2.3.2. Method for bone marrow plasma cell e6aluation
The morphological evaluation was performed on
bone marrow smear, 100 consecutive plasma cells were
analysed for these three criteria. But it is clear that the
morphologists did not identify the height subtypes by
using their pseudonyms (P111, P110 and so on). They
were working using worksheets where they just had to
put 1 or 0 for each of the three questions, cell by cell.
Some morphologists were working using a short pro-
gram on a computer. The calculator produced the
proportion of each subtypes as soon as 100 cells were
counted.
2.4. Statistical methods
The percentage of cells with one criteria (for exam-
ple, presence of nucleolus) can be sorted by increasing
value, demonstrating two waves clearly separated by a
cut-off point. This cut-off was at 25% for the nucleolus
and 66% for P000 in our two series.
All data were recorded using Dbase Software and
then transferred to PCSM Software (DeltaSoft, France)
for statistical calculations and survival studies. Survival
curves were established by the Kaplan-Meier method
1135
and compared by the logrank test. The confident inter-
val was defined as 95% and the lower limit for significa-
tion is 0.05.
3. Results
Among the 92 patients included in Study 1, two early
deaths were observed and excluded for statistical
comparison.
3.1. Response to treatment
Every patient was classified as ‘responder’ (R) and
‘non responder’ (NR). Forty-two patients had a regres-
sion of the disease (responder group) but 34 were
evaluated as non-responders. Twelve patients had to
stop their treatment for medullar toxicity and two cases
were lost for this information.
Response to treatment is demonstrated to be inde-
pendent of the morphologic subtypes. The percentage
of cells is somewhat different when considering P110
(R, 11.8%; NR, 5.4%) and P000 (R, 54.2%; NR,
64.9%), but is not statistically significant. It is also
observed that most of the time, only three subtypes are
generally identified: P000, P100 and P110. The overall
survivals (R, 43.3 months; NR, 42.4 months), survival
curves and risk of death were very similar for both
groups.
3.2. Relationship between delineated subtypes and
classical morphology
The mature plasma cell is included in the P000
subtype: nucleolus is absent, chromatin is clumped (in
blocks), and the cytoplasm is abundant. The P100
subtype is similar to P000 but shows one nucleolus
1136 J.E. Goasguen et al. / Leukemia Research 23 (1999) 1133–1140
Fig. 2. Synoptic representation of plasma cell subtypes as defined by algorithm system. P, plasma cell; first number represents presence (1) or
absence (0) of nucleolus; second number represents presence (1) or absence (0) of blastic chromatin; last number represents presence (1) or absence
(0) of N/C ratio\ 0.6.
surrounded by blocks of chromatin (P100 was com-
monly called Proplasma cell I in our group). P110 has
a nucleolus and a blastic chromatin, but cytoplasm is
large and we called it, Proplasma cell II. PB are usually
defined as having a nucleolus but some of them may be
considered as PB, even without displaying a nucleolus,
when the chromatin is blastic and the cytoplasm re-
duced. These cells are called P011 according to the
present algorithm.
3.3. Correlation between sur6i6al duration and cytology
by subtypes
3.3.1. P111
This subtype looks very similar with plasmablastic
cells as generally described [3]. To compare the method-
ologies, we tested P111 with the same cut-off of 2% as
previously used in the literature, and we compared
patients with P111 B2% and P111 ] 2%, respectively
for the outcome. This cut-off is highly discriminating
since the P value is B0.0001 for the two subpopula-
tions (Group A, all cases; Group B, restricted to re-
sponders and non responders). Results are expressed in
Table 1 and Fig. 4 for survival curves.
3.3.2. Percentage of cells with a nucleolus
Since there is a clear cut-off around 25% cells with
nucleolus, we tested this value itself for its impact on
the survival duration. Survivals were 51 months and 31
months for the two sets of 45 patients who, respec-
tively, had B 25% and ]25% cells with nucleolus
(P = 0.0330). For the group of patients (Group B)
restricted to responders and non-responders (39 and 37
cases, respectively), the survivals were 54 months and
31 months (P=0.0230).
3.3.3. Percentage of P000 (mature plasma cells)
The presence of P000 is discussed for more or less
two third of P000 cells. Forty-eight cases had less than
66% P000 and a survival duration of 31 months com-
pared to 42 cases with more than 66% P000 and 52
months survival time (P= 0.0050). When the group is
restricted to only responders (39 cases) and non-respon-
ders (37 cases) the median survivals are 31 and 60
months respectively (P=0.0050) Fig. 5.
3.3.4. Association between P000 (mature like) and
presence of nucleolus
In Group A, 40 patients associating more than 66%
P000 and less than 25% cells with nucleolus could be
compared with 43 cases with less than 66% P000 and
more than 25% cells with nucleolus. Their survivals
were 52 and 31 months respectively (P=0.0100) and,
60 and 31 months (P= 0.0080) for the group restricted
to responders and non-responders (n= 35 for both).
3.3.5. Association between P111 (plasmablastic-like)
and P000 (mature-like)
Twenty nine patients had more than 2% P111 associ-
ated with less than 66% P000 compared to 44 patients
who had less than 2% P111 and more than 66% P000.
Survival was 20 months and 52 months respectively
(PB 0.0001) for the whole group. Survival was 21 and
60 months when the groups included only responders
and non-responders (PB 0.0001) Fig. 6.
3.4. Impact of P000 on classification
Since P000 seemed to have a major impact on the
determination of new prognostic subgroups, we tested a
new proposition based on the recognition of P000.
Then, the remaining cases were classified according to
maturity of cells. According to the cells and compart-
 J.E. Goasguen et al. / Leukemia Research 23 (1999) 1133–1140 1137

Fig. 3. Synoptic representation of plasma cells as defined by new algorithm system. Cells with nucleolus are represented by P111, P110, P101,
P100. Cells with blastic chromatin are defined as P111, P110, P011, P010 and cells with very high N/C ratio (\ 0.6) are P111, P101, P011, P001.

ments evaluation we defined three groups of patients: vivals are 46, 26 and 10 months for 36, 19 and 7 cases
Group 1: P000] 66%. Then for patients with P000B respectively for Group 1, Group 2 and Group 3 (P B
66%, two groups are distinguished: Group 2: P100] 0.0001) Fig. 8.
P110+P111, and Group 3: P100B P110 + P111.
Results are displayed in Table 3 and survival curves are
shown in Fig. 7.

3.5. Control study (Study 2)

Sixty two slides were reviewed. Thirty three patients

received a conventional (as reported by IFM) therapy,
and 23 patients had intensive therapy (BMT or HD
Melphalan). There is no relation between the morpho-
logical subgroups (as defined above) and the type of
treatment (P = 0.8272). Results of the impact of the
new proposal on survival are shown in Table 2. Sur-

Table 1
Discrimination of the survival duration according to the percentage
of plasmablastic cells as evaluated by P111 (B2 or ]2%) for all cases
(A, 90 cases) and cases restricted to responders and non responders
(B, 76 cases)

P111B2% P111]2% P
Fig. 4. Survival curves for Series 1 patients restricted to responders
A n 59 31 and non-responders (76 cases). Fifty-two cases with P111 B 2% (me-
Median survival (months) 54 20 B10−4 dian 56 months) are compared to 24 patients with P111 \ 2% (me-
B n 52 24 dian 21 months). PB0.001. When all patients from Series 1 (90 cases)
Median survival (months) 56 21 B10−4 are included, medians are 54 months and 20 months, respectively
(PB0.0001).
1138 J.E. Goasguen et al. / Leukemia Research 23 (1999) 1133–1140
Fig. 5. Survival curves for Series 1 patients restricted to responders
and non-responders (76 cases). Thirty-nine cases with P000 B66%
(median 31 months) are compared to 37 patients with P000 \66%
(median 60 months). P=0.0050. Any change is observed when all
patients from Series 1 (90 cases) are included.
4. Discussion
For nearly 15 years it was well established that the
presence of plasmablastic cells was related to a poorer
prognostic in MM. Plasma cells in MM were usually
classified into four corresponding subtypes (mature,
intermediate, immature and plasmablastic) permitting
to classify patients into four subgroups. The plas-
mablastic subgroup was defined by the presence of at
least 2% of PB cells. This point can be criticised because
Fig. 6. Survival curves for Series 1 patients including responders and
non-responders and comparing patients associating P111 B 2% and
P000 \ 66% (39 cases, median 60 months) with patients having
P111 \ 2% and P000B 66% (22 cases, median 21 months) PB0.0001.
Fig. 7. Survival curves for Series 1 patients restricted to responders
and non-responders (76 cases). Group 1: 39 patients P000 \66%
(median 61 months); Group 2: 29 patients P000 B66% and P100\
P111 + P110 (median 32 months); Group 3: 8 patients P000 B 66%
and P100B P111 + P110 (median 19 months). P value for these three
groups is B 0.0001 and is unchanged when all patients from Series 1
are included (90 cases: Group 1, 44 cases, median 52 months; Group
2, 35 cases, median 32 months; Group 3, 11 cases median 20 months).
(as it was already told), it can be very difficult to
identify PB. This identification is reproducible between
experts, as it was again demonstrated in a recent report
[8] and has also been confirmed by our group. But this
identification is based on such a small number of cells
that we doubt that this message can be carried out
Fig. 8. Survival curves for Series 2 patients including 62 cases from a
single institution. As upper defined: Group 1, 36 cases, median 46
months; Group 2, 19 cases, median 26 months; Group 3, 7 cases,
median 10 months; PB0.0001.
 J.E. Goasguen et al. / Leukemia Research 23 (1999) 1133–1140
Table 2
Comparison of survival curves for multiple myeloma patients in two different studies (1 and 2) according to the proposed reclassification (Group
1, P000]66%; Group 2, P000B66% and P100\P110+P111; Group 3, P000B66% and P100BP110+P111)
P000]66%
Group 1
Study 1 Group Aa n 44
Median survival (months) 52
b
Group B n 39
Median survival (months) 61
Study 2 n 36
Median survival (months) 46
a
All 90 patients from Study 1.
b
Restricted to responder and non responder from Study 1.
through all the countries in the world. Moreover this
method allows the identification of a group including a
reduced number of patients, which represents only
around 10% [3,8] of the MM. Finally any significant
difference between the survival of the mature, intermedi-
ate and immature subgroups had also been demonstrated
meaning that this classification is restricted to worse
patients.
For these major reasons we decided to build up a new
approach for the evaluation of plasma cell morphology
based on criteria which would be easily evalu-ated and
would produce a positive (not by exclusion) evaluation
for all cells. Taking into account all possible morpholog-
ical criteria (all those already described plus: position of
the nucleus; existence of golgi-zone; size of nucleus;
aspect of chromatin) we could not obtain a valuable
reproducibility between the five observers. We excluded
some of them to keep only those that produced a valuable
concordance (\85% of cells for five morphologists).
To avoid the situation where cells are defined by
exclusion, we decided to evaluate only the criteria and not
the cell, producing this algorithm. The advantage of the
algorithm is that all cells are identified (because at the
first step they do not have a name). However four
subtypes represent 93% of the cell population (P111+
P110+P100+ P000). These cells are currently and easily
recognised since P111 is somewhat similar to PB (PB
should be P111 +P011). P110 is very close to ‘immature
myeloma cells’ [3] that we called Proplasma II, and P100
is a mature plasma cell but with a nucleolus (so-called
Proplasma I). The second advantage of the algorithm is
the recognition of 7% of cells that do not have any name.
These cells (P101, P011, P010, P001) originate the
discordance between observers because they do not fit
with any classification. In some cases, these ‘aberrant’
plasma cells may represent more than 20% of the
proliferating population (personal observation). Of
course, it was not in our goal to give them a name and
this was not necessary with the proposed procedure. But
1139
P000B66% P value
P100\P110+P111 P100BP110+P111
Group 2 Group 3
35 11
32 20 B10−4
29 8
32 19 B10−4
19 7
26 10 B10−4
the algorithm explains why the myeloma cell morphology
is so difficult to assess.
Our study reproduces some of the results already
demonstrated [3,8] because P111 and PB cells are very
close. As shown in Table 1 or Fig. 3, we found a high
correlation (P B 0.0001) between survival and P111 per-
centage meaning that this morphological evaluation is at
least as consistent as those already published.
To compare the impact of each criteria on the al-
gorithm we defined a critical value for them, keeping in
mind that the definition of a ‘cut-off’ had to be simple,
and useful. A cut-off at more or less than 25% cells with
nucleolus, is definitely significant, but the P value is only
0.0330. Each criteria by itself has a significant value but
the inclusion of three criteria for the construction of the
algorithm produces the best result, and the algorithmic
classification is drawn by the nucleolus and the chro-
matin aspect.
The key point of the preceding reports [3,8] is the
recognition of PB based on the notion that it is an index
for immaturity. In our system, the immaturity can be
assessed by P111 or P111+ P110 and so on. We tested
different combinations based on the immaturity notion,
but the most sensitive was firstly to consider the mature
compartment (which can be most easily evaluated). Since
their is a clear cut-off for patients with more or less than
two third of P000, we firstly defined the Group 1 for all
cases with P000 ] 66%. Then, (for P000 B 66%) the index
of immaturity can be evaluated for two different situa-
tions: Group 2, P100\ P110+ P111 versus Group 3,
P110+ P111\ P100. These two groups can be easily
distinguished because this is the situation where Pro-
plasma I (mature with nucleolus) are more or less
frequent than all plasma cells having a blastic chromatin
and a nucleolus (Plasmablastic+ Proplasma II).
The definition of these three subgroups is very sensitive
for the survival (P B 0.0001). The advantage of this
proposal is that if the PB are underestimated or missed,
they will be fused with P110 but the notion of immaturity
will be preserved.
1140 J.E. Goasguen et al. / Leukemia Research 23 (1999) 1133–1140
In most of the cases, the percentage of P101, P011,
P010 and P001 is very low. Since we demonstrated the
impact of the immaturity, we reclassified P101 and
P011 with the immature compartment (P111+P110)
and we gathered P010 and P001 with P000. The num-
ber of these cells being generally so small, this gathering
did not produce any change in survival curves, median
survival or statistical tests.
To be sure that the five observers did not deviate in
their evaluation, a control study was tested by a single
reviewer (JG) using the same methodology. Even
though the median survivals are somewhat different,
(Fig. 8), the sub-classification in three different groups
is highly significant (P B0.0001), providing also the
advantage to identify an intermediate subgroup repre-
senting 30% of patients (Group 1, 58%; Group 2, 30%;
Group 3, 11%).
5. Conclusion
The algorithm produces a valuable sub-classification
to demonstrate that the degree of maturity (or immatu-
rity) is a very sensitive prognostic factor. The algorithm
recognises eight subtypes but four of them are the most
frequently observed (P111, P110, P100, P000) and rep-
resent 93% of the cells. These four subtypes have been
called Plasmablastic (P111), Proplasma II (P110), Pro-
plasma I (P100) and mature plasma cell (P000) and are
easy to identify.
Finally, Group 1 is represented by patients with at
least 66% mature plasma cells (P000). Group 2 is the
intermediate group: P000B66% and Proplasma I\
PB +Proplasma II, and Group 3 is the immature group
defined as: P000B 66% and Proplasma I B PB + Pro-
plasma II (P=0.0001 for the overall survival). After
appropriated training identification of mature, ProI,
ProII and PB becomes easy. In most of the cases, the
number of ‘aberrant’ plasma cells (P101, P011, P010,
P001) is very small and the recognition of the main
proliferating cell subtypes will be discriminating. This
discussion would appear only for rare cases when a
patient may be classified as Group 2 or Group 3. For
these rare cases, the application of the algorithm is
required, but in most situations the sub-classification
can be done using only the four main cell subtypes.
Acknowledgements
J.E. Goasguen provided data, statistical expertise,
logistical support, the concept design, analysis of data,
drafted the paper, provided critical revision and gave
final approval. M. Zandecki provided data and study
materials, participated in the concept and design of the
.
project, assisted in data interpretation, drafting, revis-
ing and gave final approval to the paper. C. Mathiot
contributed to the concept and design, assisted in the
analysis of data, helped in the drafting of the paper,
critical revision and gave final approval. J.M. Scheiff,
M. Bizet, and B. Ly-Sunnaram contributed to the
concept, design, data analysis, provided study materials
and gave final approval to the article. B. Grosbois
helped to assemble the data, contributed to the concept
and design and gave fund approval to the paper. M.
Monconduit contributed to the concept and design,
provided study materials and gave final approval. J.-L.
Michaux contributed to the concept and design and
gave final approval.
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