International Journal of Myeloma 4(3): 21–27, 2014
©日本骨髄腫学会

ORIGINAL

Prognostic value of expression of CD45 and CD49d
in newly diagnosed of multiple myeloma
Kazuhito SUZUKI1, Shingo YANO1, Takaki SHIMADA1, Yuichi YAHAGI1,
Yoji OGASAWARA1, Katsuki SUGIYAMA1, Shinobu TAKAHARA1, Takeshi SAITO1,
Kinuyo KASAMA1, Hiroki YOKOYAMA1, Yutaro KAMIYAMA1, Yumiko INUI1,
Ken KAITO2, Nobuaki DOBASHI1, Noriko USUI1,3 and Keisuke AIBA1
The predictive value of surface antigens has still remained controversial after bortezomib was approved. We retrospectively analyzed patients with newly diagnosed multiple myeloma from January 2005 to June 2012 in our
department. We focused on two types of surface antigen, CD45 and CD49d, in CD38-positive myeloma cells.
Overall survival (OS) was calculated by the Kaplan-Meier method. Prognostic factors for OS were evaluated by
Cox regression analysis. Thirty-seven patients were enrolled into this study. The median follow-up time was 20.2
months. There tended to be a difference of OS among four groups, CD45–CD49d+, CD45+CD49d+, CD45–CD49d–,
and CD45+CD49d– (log-rank test; p = 0.051). Patients were classified into two groups based on the expression
patterns of CD45 and CD49d. While median OS in CD45–CD49d+ patients was not reached yet, median OS in
non-CD45–CD49d+ patients was 25.2 months (95% CI, 14.6–35.8 months), respectively (log-rank test; p = 0.014).
Multivariate analysis revealed that CD45–CD49d+ was the independent prognostic factor for longer survival (hazard
ratio 0.064. 95% CI 0.006–0.643; p = 0.020). In conclusion, the expressions of CD45–CD49d+ seemed to be a favorite
OS in multiple myeloma patients.
Key words:

multiple myeloma, CD45, CD49d, flow cytometry, bortezomib, CAM-DR

became available 2). But, the predictive value of surface anti-

Introduction

gens has been controversial in the era of bortezomib.
Multiple myeloma is characterized by a clonal human

During plasma cell development, it has been well-known

plasma cell neoplasm and develops mainly in bone marrow.

that progressive loss of B-cell markers, such as CD19 and CD20,

Myeloma cells appear to be heterogeneous in terms of theand the acquisition of markers, such as CD138 and CD56, con-1)

expression of surface antigens and biological characteristics .

fer malignant phenotype on plasma cells 3). CD45 is the leuko-

Analysis of surface antigens by flow cytometry (FCM) had beencyte common antigen and can be found on all hematopoietic

reported as one of predictors for prognosis before bortezomib

cells but not on red blood cells or platelets 3). Most of myeloma
cells do not express CD45, but immature proliferating

Received: November 18, 2013, accepted: May 13, 2014
1
Division of Clinical Oncology/Hematology, Department of Internal
Medicine, the Jikei University School of Medicine
2
Central Clinical Laboratory, the Jikei University Hospital
3
Division of Transfusion Medicine, the Jikei University School of
Medicine
Corresponding author: Keisuke AIBADivision of Clinical Oncology/Hematology, The Jikei University
School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo
105-8461, Japan
TEL: 81-3-3433-1111, FAX: 81-3-3436-3233
E-mail: aiba@jikei.ac.jp

myeloma cells express CD45 2). Kumar S et al. had reported thatthe median overall survival (OS) in CD45+ patients tended to
be longer than that in CD45– patients 4). CD49d is a subunit ofvery late antigen-4 (VLA-4), which was identified as a criticalmolecule for the induction of cell adhesion-mediated drug
resistance (CAM-DR). The interaction between myeloma cells
and neighboring stromal cells which express vascular celladhesion molecule-1 (VCAM-1) enhances the production offactors for osteoclastogenesis, and the disruption of this cellto-cell contact by neutralizing antibody against VCAM-1
suppresses osteoclastogenic activity 5,6). Myeloma patients withprimary multidrug resistance showed significantly higher

International Journal of Myeloma

vol. 4 no. 3 (2014)21

Suzuki et al.

concentrations of serum VLA-4 and intercellular adhesion

serum/urine M-protein detectable by immunofixation but notmolecule-1 (ICAM-1) than those with the higher sensitivity toon electrophoresis or ≥90% reduction in serum M-protein plus

7)

anti-myeloma drugs . However, in vitro analyses showed thaturine M-protein <100 mg per 24 hours. Partial response (PR)bortezomib may be effective in ameliorating CAM-DR throughwas defined as having ≥50% reduction of serum M-protein

8)

downregulation of VLA-4 expression in myeloma cells .

and reduction of 24-hour urinary M-protein by ≥90% or to

We analyzed the expression of CD45 and CD49d on multiple<200 mg per 24 hours. Progressive disease (PD) was defined as

myeloma cells at initial diagnosis. The purpose of this retro->25% increase in M-protein on two separate measurements atspective study was to investigate the prognostic value of these

4-week intervals. Stable disease (SD) was not meeting thesurface antigens.

criteria for CR, VGPR, PR, or PD 10).

Methods

Flow cytometry analysis
FCM analysis was performed in the single laboratory atPatients

Special Reference Laboratories, Inc. (SRL, Tokyo Japan). Two

We retrospectively analyzed thirty-seven patients withtypes of antibodies were used: CD45 and CD49d for CD38

newly diagnosed multiple myeloma from January 2005 topositive cells. These expressions were evaluated by two-color

June 2012 at the Jikei University Hospital. This study waspanel of antibodies.

approved by the Independent Ethics Committee/Institutional
Review Board in our institute. Patients provided written

Statistical analysis

informed consent before entering the studies, which were

OS was defined as time from diagnosis to death resulting

carried out in accordance with the Declaration of Helsinki.

from any cause. Univariate analysis was performed for each ofMedian age was 65 (range: 51–88) years old and all patientsthe parameters indicated above. OS was analyzed by using

had symptomatic multiple myeloma. Symptomatic multiple

Kaplan-Meier methodology, and differences of OS between

myeloma was defined by serum monoclonal protein ≥3 g/dLgroups were assessed with the log-rank test. We analyzed

or bone marrow plasma cells ≥10% with any of the CRAB

prognostic factors for OS, such as surface antigens, age, ane-

(CRAB; calcium elevation, renal insufficiency, anemia andmia by the CRAB criteria, renal failure by the CRAB criteria, thebone disease) criteria, such as an elevation of serum calcium

International Staging System (ISS) 11), cytogenetic abnormality,(>11.5 mg/dL), renal insufficiency (serum level of creatinine

bortezomib containing induction therapy, and autologous>2 mg/dL), anemia (hemoglobin concentration <10 g/dL orstem cell transplantation, using Cox regression analysis. The

2 g/dL less than the lower normal limit) and lytic or osteopenic

chi-square and Fisher’s exact tests were used to compare dif-bone disease 9).

ferences between two groups. All p-values were two-sided,and statistical significance was defined as p < 0.05. The statis-

Treatment and assessment of response
All patients received standard regimens of induction ther-tical analyses were computed with SPSS statistical software(SPSS Inc., Chicago, IL).

apy, such as bortezomib plus dexamethasone (BD), vincristine,

Resultsadriamycin plus dexamethasone (VAD), melphalan plus predonisolone (MP), or high-dose dexamethasone (HDD). Eightpatients received high-dose melphalan followed by autolo-

Patients

gous peripheral blood stem cell transplantation. Patients who

We analyzed thirty-seven patients with multiple myeloma.

relapsed or had refractory disease received salvage therapy

The patient characteristics are shown in Table 1. The classifica-of BD, cyclophosphamide, bortezomib plus dexamethasone

tion of the ISS was as follows: 9 had ISS 1, 17 had ISS 2, 8 had(CVD), melphalan, bortezomib plus predonisolone (MBP),

ISS 3, and 3 had no available data. Nine patients had cyto­bortezomib, lenalidomide plus dexamethasone (BLD), lenalid-

genetic abnormality by Q bands analysis, 7 had hyperdiploid,omide plus low-dose dexamethasone (Ld), thalidomide plus

1 had hypodiploid, 1 had t(11;14), 1 had del(17), and 2 had –Y.

dexamethasone (TD), ranimustine, vincristine, melphalan plus
dexamethasone (ROAD), MP, HDD, or VAD. Evaluation of

Flow cytometry analysis

response was carried out based on the following criteria.

Plasma cells were identified by strong expression of CD38.

Complete response (CR) was defined as having negative

Among thirty-seven patients, the median percentages of CD19,

serum/urine immunofixation, the disappearance of any soft

CD45, CD49d, CD49e, and CD56 positive cells were 2.0%

tissue plasmacytomas and ≤5% plasma cells in bone marrow.

(range, 0.1–63.9%), 22.6% (range, 0.9–100), 86.9% (range,

Very good partial response (VGPR) was defined as having

0.7–99.2), 1.7% (range, 0.0–47.7), and 87.5% (range, 1.2–99.7),

22International Journal of Myeloma

vol. 4 no. 3 (2014)

CD45 and CD49d in multiple myeloma

Table 1.

Patient characteristics

All patients

CD45–CD49d+

Median≤65 yr>65 yr24
13

65 yr (51–87)
10
4

14
9

.387

Gendermale
female

20
17

7
7

13
10

.481

M protein subtype
IgG
IgA
BJP
others

24
6
6
1

7
3
4
0

17
3
2
1

.092

International Staging System
1
2
3
NA

9
17
8
3

3
6
3
2

6
11
5
1

.598

Anemia according to CRAB criteria
positive
negative

28
9

12
2

16
7

.241

Renal failure according to CRAB criteria
positive
negative

3
34

0
14

3
20

Serum level of LDH
>UNL
≤UNL

5
32

3
11

2
21

.269

Serum level of CRP
>UNL
≤UNL

20
17

8
6

12
11

.519

Bortezomib containing Induction Therapy
Yes
No
MP
VAD
HDD

9
28
18
7
3

3
11
6
4
1

6
17
12
3
2

.536

Autologous stem cell transplant
Yes
No

7
30

4
10

3
20

.228

Cytogenetics
normalabnormal*
NA

22
9
6

7
4
2

15
5
4

.204

CD45+CD49d+
CD45–CD49d–
CD45+CD49d–

P value

Age* Cytogenetic abnormality by Q-binding method were 7 of hyperdiploid, 1 of hypodiploid, 1 of t(11;14), 1 of del17, and –Y; 2.
BJP; Bence Jones protein, NA; not available, ISS; International Staging System, CRAB; calcium elevation, renal insufficiency,
anemia and bone disease, LDH; lactase dehydrogenase, CRP; C-reactive protein, MP; melphalan plus predonisolone, VAD;
vincristine, adriamycin plus dexamethasone, HDD; high-dose dexamethasone, UNL; upper normal limit, NA; not available.

respectively. We focused on the correlation between OS and

20% and 50%, respectively. Eighteen out of 37 patients had

the expressions of CD45 and CD49d. In this study, the cut-off

CD45+ plasma cells. Thirty patients expressed CD49d+ and 7

levels for CD45 positivity and CD49d positivity were defined as

had CD49d–.

International Journal of Myeloma

vol. 4 no. 3 (2014)23

Suzuki et al.

Table 2.

Chemotherapy and response

All patients

CD45–CD49d+

CD45+CD49d+
CD45–CD49d–
CD45+CD49d–

19
13
0
6
13
10
3
2

8
3
0
4
4
1
2
2

11
10
0
2
9
9
1
0

Response by Induction Therapy
PR or better
SD or less
CR
VGPR
PR
SD
PD
NA

P value.233

PR; partial response, SD; stable disease, CR; complete response, VGPR; very good partial response, PD; progression disease,
NA; not available.

Figure 1. a. The overall survival in CD45+ patients and CD45– patients. There was no significant difference in overall survival between CD45+
patients and CD45– patients (p = 0.201). b. The overall survival in CD49d+ patients and CD49d– patients. There was no significant differencein overall survival between CD49d+ and CD49d– (p = 0.212). c. The overall survival in CD45–CD49d+ patients, CD45+CD49d+ patients,
CD45–CD49d– patients, and CD45+CD49d– patients. There tended to be significant difference of overall survival in four groups, CD45–
CD49d+ patients, CD45+CD49d+ patients, CD45–CD49d– patients, and CD45+CD49d– patients (log-rank test; p = 0.051). d. The overall­survival in CD45–CD49d+ patients compared with those in CD45+CD49d+ patients, CD45–CD49d– patients, and CD45+CD49d– patients.
Overall survival in CD45–CD49d+ patients was significantly longer than those in CD45+CD49d+ patients, CD45–CD49d– patients, andCD45+CD49d– patients (log-rank test; p = 0.014).

24

International Journal of Myeloma

vol. 4 no. 3 (2014)

CD45 and CD49d in multiple myeloma

Table 3. The multivariate analyses for overall survival
FactorCD45– and CD49d+
CD45+CD49d+, CD45–CD49d–, CD45+CD49d–
Age > 65 yr
Age ≤ 65 yr
Anemia by CRAB criteria

Hazard ratio (range)

P value.064 (.006–.643)

.020

1.0
.985 (.167–5.804)
1.0
3.299 (.511–21.299)

non-anemia by CRAB criteria

1.0

Renal failure by CRAB criteriaNAnon-renal failure by CRAB criteria
ISS 3
ISS 1, 2
Cytogenetic abnormality positive
Cytogenetic abnormality negative
Bortezomib containing Induction Therapy
non-Bortezomib containing Induction Therapy
Autologous stem cell transplantnon-Autologous stem cell transplant

.986
.210
.990

1.0
2.351 (.191–28.959)

.505

1.0
1.380 (.212–8.978)

.736

1.0
2.185 (.176–27.115)

.543

1.0
.683 (.096–4.834)

.702

1.0

CRAB; calcium elevation, renal insufficiency, anemia and bone disease, ISS; international staging system,
NA; not available.

Response to induction therapy

as age, anemia by the CRAB criteria, renal failure by the CRAB

Response to induction therapy is shown in Table 2. As induc-criteria, ISS, cytogenetic abnormality, bortezomib containing

tion therapy, nine patients received BD, 18 MP, 7 VAD, and 3

induction therapy, and autologous stem cell transplantation,

HDD. Overall response rates of all patients and the patientsin this model demonstrated that CD45–CD49d+ was an

who received BD were 51.4% and 66.7%, respectively. Three

independent prognostic factor for OS (hazard ratio 0.064.

patients discontinued induction therapy: 1 was because of

95% CI 0.006–0.643; p = 0.020) (Table 3).

peripheral neuropathy due to BD, 1 was respiratory failure due
to MP, and 1 was poor performance status due to MP. Seven

Discussion

patients received autologous stem cell transplant when thepatients had obtained equal to or better than PR.

This study suggested that OS was significantly better inthe patients with CD45–CD49d+ on myeloma cells. Several

Survivalwell-known prognostic predictors of newly diagnosed multi-

Median follow-up time was 20.2 months (range, 4.2–99.1).

ple myeloma have been ISS 11), Durie and Salmon system 12),First, we compared OS between CD45+ patients and CD45–

abnormal cytogenetics 13–18), and gene expression profiling 19,20).

patients, and between CD49d+ and CD49d–. There were no

However, the prognostic values of surface antigens have beensignificant difference of OS between CD45+ patients andcontroversial since bortezomib was approved.

CD45– patients, and between CD49d+ and CD49d–, respec-

CD45 is a leukocyte common antigen expressed on all

tively (p = 0.201, and 0.212, Fig. 1a, 1b). Next, we evaluated OS

hematopoietic cells except for both mature erythrocytes andin respective four groups, CD45–CD49d+, CD45+CD49d+,

platelets. CD45 molecule is expressed on all nucleatedCD45–CD49d–, and CD45+CD49d– patients. There tended tohematopoietic cells, whereas the expression of CD45 mole-exist different OS among four groups (log-rank test; p = 0.051,

cules on primary myeloma cells and cell lines is quite vari-Fig. 1c). The survival of CD45–CD49d+ patients tended to beable, a finding consistent with the heterogeneity of myeloma

better than the others, and OS in CD45–CD49d+ patients wascells 21). Human myeloma cells isolated from patients are potent

significantly better than those in non-CD45–CD49d+ patientsin responding to cytokines, including interleukin-6 (IL-6), and(p = 0.014, Fig. 1d). Median OS in CD45–CD49d+ patients wasare able to proliferate in in vitro 22). The CD45+ myeloma cells

not reached, but median OS in non-CD45–CD49d+ patients

appear to be more proliferative in response to IL-6 than CD45–

was 25.2 months.

cells 2,23,24). In addition, IL-6 modulates the expression of CD45

Multivariate analysis of the seven prognostic factors, suchon myeloma cells 23). Kumar S et al. reported that CD45+

International Journal of Myeloma

vol. 4 no. 3 (2014)25

Suzuki et al.

cells increased significantly in patients with monoclonaland CD49d+ tended to be longer than that in the patients

gammopathy of undetermined significance (MGUS) andwithout CD45+ and CD49d– (p = 0.074). In multivariate analy-­smoldering myeloma compared with those in newly diag-sis, the phenotype of CD45–CD49d+ was a favorable prognos-

nosed myeloma and relapsed myeloma cells. Median OS intic factor for OS. In this study, a total of 13 patients died andCD45+ patients tended to be longer than that in CD45–

the causes of death were myeloma in 8, amyloidosis in one,patients 4). These differences of OS in our result and the pre­sepsis in one, liver failure in one, hypoglycemia in one, andvious report were not significant. Moreover, in our patients,

unknown in one. In the CD45–CD49d+ group, only 1 patient

there was no significant difference in overall response rate

died of myeloma, while in the non-CD45–CD49d+ group,

between CD45+ and CD45– patients (p = 0.630).

deaths from other causes than myeloma were observed. This

CD49d is a subunit of VLA-4, a heterodimer of CD49d/CD29.

might contribute to short-term survival in the non-CD45–

VLA-4 is an unusual β1 integrin expressed on resting lympho-

CD49d+ group. In addition, we analyzed morphological find-cytes, monocytes and neural crest-derived cells, and functions

ings in twelve bone marrow samples according to the Griepp’s

as both a matrix and cell receptor. VLA-4 binds to molecules

criteria. Unfortunately, the other twenty-five bone marrowsuch as VCAM-1, which is a member of the immunoglobulin

samples were not available (due to a huge earthquake insuperfamily. VCAM-1 is induced by inflammatory mediators

March 2011). In patients with CD45–CD49d+ myeloma cells,on the endothelium with kinetics similar to ICAM-1, and inter-three patients had mature myeloma cells, and three had

action with VLA-4 provides an explanation for the earlier

immature myeloma cells. In patients without CD45–CD49d+

evidence of a second lymphocyte-endothelium adhesion

myeloma cells, three patients had mature myeloma cells, one

25)

mechanism distinct from the LFA-1/ICAM interaction . VLA-

had intermediate myeloma cells, one had immature myeloma

4-mediated signaling is important for the development of incells, and one had blastic myeloma cells. There were no sig-

26)

vitro CAM-DR in myeloma cells . It has been reported thatnificant correlation between CD45–CD49d+ positivity andmyeloma patients with primary multidrug resistance showed

myeloma cell morphology according to the Griepp’s criteria

significantly higher serum concentration of VLA-4 and ICAM-1(p = 0.716). Finally, the average level of serum creatinine inthan those with responders 6). Moreover, administration of

non-CD45–CD49d+ arm was higher than that in CD45–

anti-α4 integrin antibody suppressed the growth of myeloma

CD49d+ arm (0.99 mg/dL vs 1.70 mg/dL, p = 0.048) by t-test.

cells in a murine xenograft 27,28). It has been reported that

The average level of serum beta2-microgloburin in non-CD45–

bortezomib overcomes CAM-DR through downregulation ofCD49d+ arm tended to be higher than CD45–CD49d+ arm

the expression of CD49d, a subunit of VLA-4 in in vitro 7,29).

(4.4 mg/dL vs 6.4 mg/dL, p = 0.074) by t-test. The patients with

However, there has been no data that bortezomib could over-

CD45–CD49d+ myeloma cells might be better renal function

come CAM-DR in vivo. In our patients, there was no significant

than those without CD45–CD49d+ myeloma cells. However,difference between expression of CD49d and response rate by

our trial was a small retrospective trial and the results werebortezomib containing regimens as induction therapy. High

therefore limited. Possibility of the prognostic value of expres-

CD49d expression was not associated with a poor responsesions of CD45 and CD49d on myeloma cells need to be neces-(p = 0.233). Thus, CAM-DR might not be identified among

sary to be investigated on a well-designed large clinical trial.

patients with CD49d+ in in vivo.

In conclusion, the expression of CD45–CD49d+ by FCM

In this study, the cut-off levels for CD45 positivity andmight be predictive factor for a favorite outcome among

CD49d positivity were defined as 20% and 50%, respectively.

patients with multiple myeloma. However, our sample size was

We defined as the cut-off of CD45 positivity as 20% according

small, and larger-scale research would be needed to confirm

to previous reports. However, only two patients had CD49d

prognostic value of expression of CD45 and CD49d inpositive plasma cells in case the cut-off level of CD49d positiv-

myeloma patients.

ity was defined as 20%. Median percentage of CD49d positivity

Acknowledgements

was 86.9% in all patients and the percentage of CD49d positive plasma cells was 50% or more among the majority ofpatients. Therefore, we defined as the cut-off level of CD49d

nurses at the Hospital of the Jikei University School of Medi-

positivity as 50%.
In our patients, CD45–CD49d+ patients significantly survived longer than non-CD45–CD49d+ patients, while there
were no significant difference in overall response rate between
CD45–CD49d+ and non-CD45–CD49d+ patients (p = 0.233).
Moreover, the response duration in the patients with CD45–
26

International Journal of Myeloma

We thank our attending doctors, dedicated fellows, andvol. 4 no. 3 (2014)

cine. We offer special thanks to our multiple myeloma patientsand their families.

CD45 and CD49d in multiple myeloma

Conflict of Interest
The authors declared no potential conflicts of interest.

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International Journal of Myeloma

vol. 4 no. 3 (2014)27