ORIGINAL ARTICLE
Limited value of the international staging system for predictinglong-term outcome of transplant-ineligible, newly diagnosed,symptomatic multiple myeloma in the era of novel agents
Junya Kuroda • Yuji Shimura • Kensuke Ohta • Hirokazu Tanaka • Hirohiko Shibayama •
Satoru Kosugi • Shinichi Fuchida • Masayuki Kobayashi • Hitomi Kaneko • Nobuhiko Uoshima •
Kazuyoshi Ishii • Shosaku Nomura • Masafumi Taniwaki • Akifumi Takaori-Kondo •
Chihiro Shimazaki • Mitsuru Tsudo • Masayuki Hino • Itaru Matsumura • Yuzuru Kanakura •
Kansai Myeloma Forum Investigators
Received: 24 December 2013 / Revised: 12 February 2014 / Accepted: 13 February 2014
� The Japanese Society of Hematology 2014
Abstract We retrospectively investigated clinical out-
comes and prognostic factors of 131 patients with transplant-
ineligible newly diagnosed multiple myeloma (NDMM)
who received melphalan and prednisolone (MP) as first-line
therapy from 2006 to 2013. Eighty-one patients received
salvage therapies incorporating bortezomib, lenalidomide,
and/or thalidomide. The overall response rate to MP was
54.2 %, including 9.2 % of better than very good partial
response. With a median follow-up period of 30.2 months,
median overall survival (OS) and median time to next
treatment (TNT) were 54.4 and 19.0 months, respectively.
Univariate analysis revealed that performance status and
serum calcium level significantly associated with both OS
and TNT, and multivariate analysis revealed that the higher
serum calcium level had a significantly unfavorable impact
on OS and TNT. Importantly, staging informed by the
international staging system (ISS) was not predictive for OS
or TNT in the analyzed cohort. Our study revealed that, in the
context of first-line MP therapy for NDMM, the salvage
therapy incorporating novel agents produced a survival
period of [30 months after the initiation of second-line
therapy, suggesting that the predictive value of ISS for OS
and TNT may be limited in the era of novel agents.
Keywords Multiple myeloma � Melphalan �Prednisolone � Novel agent � International staging system
Introduction
Multiple myeloma (MM), which originates from post-
germinal center B cells, is the second most common
hematological malignancy and constitutes 1 % of all
cancers. Although MM remains mostly incurable, the
J. Kuroda and Y. Shimura contribute equal to this study.
Electronic supplementary material The online version of thisarticle (doi:10.1007/s12185-014-1539-5) contains supplementarymaterial, which is available to authorized users.
J. Kuroda (&) � Y. Shimura � M. Taniwaki
Division of Hematology and Oncology, Department of
Medicine, Kyoto Prefectural University of Medicine,
465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan
e-mail: [email protected]
K. Ohta
Department of Hematology, Osaka Saiseikai Nakatsu Hospital,
2-10-39 Shibata, Kita-ku, Osaka 530-0012, Japan
H. Tanaka � I. Matsumura
Department of Hematology and Rheumatology, Kinki University
Faculty of Medicine, Sayama, Osaka 589-8511, Japan
H. Shibayama � Y. Kanakura
Department of Hematology and Oncology, Osaka University
Graduate School of Medicine, Suita, Osaka 565-0871, Japan
S. Kosugi
Department of Internal Medicine, Toyonaka Municipal Hospital,
Toyonaka, Osaka 560-8565, Japan
S. Fuchida � C. Shimazaki
Department of Hematology, Social Insurance Kyoto Hospital,
Kyoto 603-8151, Japan
M. Kobayashi � A. Takaori-Kondo
Department of Hematology and Oncology, Graduate School of
Medicine, Kyoto University, Kyoto 606-8507, Japan
H. Kaneko � M. Tsudo
Department of Hematology, Osaka Red Cross Hospital,
Osaka 543-8555, Japan
123
Int J Hematol
DOI 10.1007/s12185-014-1539-5
treatment outcome of MM has been greatly improved
during this decade by the introduction of novel anti-MM
agents, such as proteasome inhibitor (PI), bortezomib and
immunomodulatory drugs (IMiDs) such as thalidomide
and lenalidomide [1, 2]. It is expected that the use of
upcoming new agents, such as a novel PI carfilzomib [3,
4], a novel IMiD pomalidomide [5, 6] or biologic agents
of monoclonal antibodies such as elotuzumab and dar-
atumumab [7, 8], will further improve treatment out-
comes. In this era of series of novel agents, a critical
current and future topic regarding anti-MM treatment is
and will be the establishment of a therapeutic strategy
which makes the most of currently available anti-MM
agents by concurrently and/or sequentially incorporating
both novel agents and traditional cytotoxic agents, such
as alkylators, anthracyclines or vinca alkaloids.
In Japan, bortezomib, thalidomide and lenalidomide
were initially approved for the treatment of relapsed/
refractory MM (RRMM) only, and the use of both thalid-
omide and lenalidomide remains limited to RRMM even at
the timing of writing in 2014. Therefore, most transplant-
ineligible patients received melphalan and prednisolone
(MP) therapy as the first-line strategy until the approval of
bortezomib as the first-line agent in September 2011. This
enabled us to investigate the clinical outcome of newly
diagnosed MM (NDMM) patients who received traditional
MP therapy as the first-line strategy even in the era of novel
agents, as well as the role of the salvage therapy with novel
agents in the context of the first-line MP. Since its devel-
opment in the late 1950’s, MP therapy has been the gold
standard of anti-MM chemotherapeutic regimens until the
introduction of novel agents in this century [9, 10]. The
dosages of melphalan and prednisolone for MP therapy
have varied depending on the discretion of individual
physicians and institutes and even among well-designed
clinical trials. Generally, 0.18–0.25 mg/kg or 7–9 mg/m2
of melphalan and 40–100 mg/body or 1–2 mg/kg pred-
nisolone for 4 days per cycle were administered every
4–6 weeks, but the response rate and the long-term out-
come did not differ widely among the various protocols.
The overall response rates (ORR), i.e., the achievement of
better than partial response (PR), with MP were 33–55 %
and the median progression free survival (PFS) and median
overall survival (OS) were 11–20.7 and 29.4–49.4 months,
respectively [11–19]. Especially, without the aid of novel
agents as the salvage therapy, OS of NDMM patients was
2.5–3 years in the setting of MP as the first-line therapy
[20, 21]. For the development of future novel therapeutic
strategies, it is essential to be able to share information
regarding the potency and limitations of sequential therapy
consisting of initial therapy with traditional MP therapy
and subsequent therapy with new agents. In fact, the more
favorable effects of several novel concurrent combination
strategies incorporating MP and bortezomib or MP and
IMiDs have been already validated by comparative studies
using MP only in large clinical trials [11–19], so that future
clinical trials may no longer be concerned with the treat-
ment arm of MP therapy by itself for clinical as well as
ethical reasons. In other words, future clinical studies will
not continue to provide information regarding the long-
term outcome of patients who are sequentially treated with
MP as the first-line and then with novel agents as salvage
treatment. In this study, we retrospectively investigate the
long-term outcome and prognostic factors for 131 NDMM
patients in the era of new agents in the context of the first-
line treatment with MP.
Materials
Patients and study design
This study was conducted in accordance with the ethical
principles of the Declaration of Helsinki, and was
approved by the institutional review boards of all insti-
tutes participating in the Kansai Myeloma Forum (KMF).
Between January 2006 and March 2013, a total of 175
patients were diagnosed as symptomatic NDMM and
received MP therapy as the first-line chemotherapy.
Asymptomatic MM patients were excluded from this
analysis. As described above, the dosages of melphalan
and prednisolone and the treatment interval depended on
physicians’ or institutes’ discretion. In general, 6–9 mg/m2
of melphalan and 40–60 mg/m2 of prednisolone for 4 days
were administered every 4 weeks. The use of bisphos-
phonates was permitted. For the assessment of OS and
time to next treatment (TNT), the patients’ clinical
records were reviewed for retrospective analysis of the
data for age, gender, performance status (PS) according to
the Eastern Cooperative Oncology Group (ECOG) criteria,
paraprotein type, the disease stage according to the
International Staging System (ISS) [22], laboratory data
including b2 microglobulin, serum creatinine, hemoglobin,
serum calcium and serum albumin, response to therapy
according to the International Myeloma Working Group
N. Uoshima
Department of Hematology, Matsushita Memorial Hospital,
Moriguchi, Osaka 570-8540, Japan
K. Ishii � S. Nomura
First Department of Internal Medicine, Kansai Medical
University, Moriguchi, Osaka 570-0074, Japan
M. Hino
Department of Hematology, Graduate School of Medicine,
Osaka City University, Osaka 545-8585, Japan
J. Kuroda et al.
123
criteria [23] as well as clinical outcome and types of
salvage therapies. In addition, myeloma cell ratio of bone
marrow, the number of bone lesions which was detectable
by routine X-ray-based systemic bone survey and presence
of extramedullary lesions were analyzed in relation to the
degree of response to MP therapy, when data were
available in complete group.
Statistical analysis
Patient survival was analyzed with the Kaplan–Meier
method and results were compared by means of log-rank
statistics and Cox proportional hazards model. Variables
were evaluated with the Mann–Whitney U test, or Fisher’s
exact test. A p value \0.05 was considered statistically
significant. All calculations were performed with EZR
(modified R software, Saitama Medical Center, Jichi
Medical University, Saitama, Japan).
Results
Patients
Of 175 NDMM patients who received MP as the first-
line therapy, complete data sets were available for 131
patients (complete group), while at least one datum was
missing for 44 patients (incomplete group). The patients’
background, such as age and gender, of complete group
was not significantly different from that of total patients,
and, thus, the following analyses were performed on 131
patients of complete group. The 131 NDMM patients in
complete group comprised 60 males and 71 females with
a median age at diagnosis of 74 years old, 78 of whom
had immunoglobulin (Ig) G type paraprotein, 37 had IgA
type, and 16 had other types (Bence-Jones, IgD and
IgM). Disease stage according to the ISS was as follows:
stage 1, 2 and 3 accounted for 28.2, 48.1 and 23.7 %,
respectively. Ninety-five patients (72.5 %) were PS 0–1
and 36 patients (27.4 %) were unfavorable PS 2–4. Bone
lesions of 117 and extramedullary lesions of 108 patients
were evaluable in complete group, showing that 41.8 %
had more than two bone lesions and 11.1 % had at least
one extramedullary lesion (Table 1). Forty patients did
Table 1 Patients’ background and best response to MP therapy
All NDMM patients who received MP as the first-line in KMF
Total number of patients (n) 175
Age, years, median (range) 74 (33–91)
Gender, male: female (n) 77:98
Paraprotein type, IgG:IgA: others (n) 105:43:27
Disease stage determined by ISS 1, 2, 3, NA (n) 37:71:35:32
Performance status, 0:1:2:3:4: NR(n) 68:52:30:7:3:15
Patients with more than two bone lesion (%) 40.2
Patients with extramedullary lesion (%) 8.3
Best response to MP therapy, CR, VGPR, PR,
SD, PD, NE (n)
9:7:65:70:8:16
NDMM patients who received MP as the first-line and were selected
as complete group
Total number of patients with complete data (n) 131
Age, years, median (range) 74 (33–91)
Gender, male: female (n) 60:71
Paraprotein type, IgG:IgA: others (n) 78:37:16
Disease stage determined by ISS 1, 2, 3 (n) 37:63:31
Performance status, 0:1:2:3:4 (n) 54:41:28:5:3
Patients with more than two bone lesion (%) 41.8
Patients with extramedullary lesion (%) 11.1
Best response to MP therapy, CR, VGPR, PR,
SD, PD (n)
5:7:53:58:8
NDMM newly diagnosed multiple myeloma, MP melphalan and
prednisolone, KMF Kansai Myeloma Forum, NA not evaluable due to
the lack of data at diagnosis; NR not recorded exactly; NE not yet
evaluable, under treatment
0 20 40 60 80
0.0
0.2
0.4
0.6
0.8
1.0
Months
Pro
babi
lity
0 20 40 60 80
0.0
0.2
0.4
0.6
0.8
1.0
Months
Pro
babi
lity
OS TNTa b
Fig. 1 Overall survival (OS) and time to next treatment (TNT)
periods for 131 patients with newly diagnosed symptomatic multiple
myeloma (NDMM) at institutes participating in the Kansai Myeloma
Forum (KMF) who were treated with melphalan and prednisolone
(MP) as the first-line strategy. OS (a) and TNT (b) were analyzed
with the Kaplan–Meier method
Value of ISS for NDMM in the era of new agents
123
not have bone lesions and 77 possessed at least one
pathologic bone lesion, including pathologic bone frac-
ture, focal osteolytic lesion and osteopenia, while 32
patients presented with unfavorable PS 2–4. As a result,
6 of 40 patients without bone lesion (15.0 %) and 26 of
77 patients with bone lesion (33.8 %) presented with PS
2-4 at diagnosis. The median age of patients with
unfavorable PS 2–4 (77.0 years old) was statistically
significantly older than that of patients with favorable PS
0–1 (72.0 years old) (p \ 0.001), while PS 2–4 was not
statistically significantly associated with the presence of
bone lesion (p = 0.322).
Response to the first-line MP therapy and long-term
outcome of NDMM patients treated with first-line MP
therapy
The median cycle of MP therapy for our cohort was 5.5
(range 1–44). The overall response rate (ORR) to MP was
54.2 % with 3.8 % of patients showing complete response
Fig. 2 Effect of variables on
OS and TNT of NDMM patients
treated with MP as the first-line
strategy. a OS of patients over
75 years old (black) and below
75 years old (blue), b OS of
patients with performance status
(PS) 0–1 (blue) and 2–4 (black),
c OS according to the serum
calcium (Ca) level below
11.0 mg/dL (blue) and over
11.0 mg/dL, d TNT for patients
over 75 years old (black) and
below 75 years old (blue),
e TNT for patients with PS 0–1
(black) and PS 2–4 (blue), and
f TNT according to the serum
Ca level below 11.0 mg/dL
(blue) and over 11.0 mg/dL
J. Kuroda et al.
123
(CR) and 5.3 % very good partial response (VGPR). Due to
loss of response to MP therapy, 81 patients (61.8 %)
underwent subsequent salvage therapies incorporating the
novel agents bortezomib, lenalidomide and/or thalidomide
(bortezomib alone; n = 25, lenalidomide alone; n = 14,
thalidomide alone; n = 4, bortezomib and lenalidomide;
n = 11, bortezomib and thalidomide; n = 13, lenalido-
mide and thalidomide; n = 3, bortezomib, lenalidomide
and thalidomide; n = 11). The resultant median OS and
median TNT were 54.4 and 19.0 months, respectively, with
a median observation period of 30.2 months in complete
group (Fig. 1a, b). In addition, neither OS nor TNT of the
complete and incomplete groups was significantly different
(Supplemental Fig. 1a, b).
Serum calcium level, PS, and the response to MP,
but not ISS, were predictive for long-term outcome
We analyzed factors predictive for the long-term outcome
of NDMM patients treated with first-line MP therapy in the
era of novel agents. Univariate analyses revealed that
patient age, PS and serum calcium level were predictive for
OS (Fig. 2a, c, e; Table 2), while PS and serum calcium
level were predictive for TNT with the first-line MP ther-
apy (Fig. 2d, f; Table 2). Importantly, multivariate analysis
revealed that the only serum calcium level over 11.0 mg/
dL was the significant unfavorable prognostic factor for
both OS (p = 0.009) and TNT (p = 0.018). Although TNT
of patients with ISS stage 2/3 tended to be inferior than that
of patients with ISS stage 1, ISS-determined disease stage
did not show a significant impact on OS or TNT in our
cohort (Fig. 3a, b; Table 2).
Next, we examined the effect of the degree of the
response to MP on the long-term outcome for NDMM
after treatment with MP as the first-line therapy. The
response to MP therapy was not influenced by the ISS-
determined disease stage (Fig. 4a). Both OS and TNT of
patients who attained better than VGPR were not
reached, while OS and TNT of patients who attained
worse than partial response (PR) were 50.1 and
17.0 months, respectively. As a result, both OS and TNT
of patients who achieved better than VGPR were,
therefore, significantly longer than for those who attained
worse than PR (OS; p = 0.023, TNT; p \ 0.001)
(Fig. 4b, c). There was no significant difference between
OS and TNT of the patients who attained CR and those
who attained VGPR (Fig. 4d, e).
Difference between good responders and poor
responders to MP therapy at diagnosis
We finally analyzed factors which discriminate the
response to MP therapy by comparing patients who
achieved CR/VGPR, PR/SD, and progressive disease
(PD) as the best response. PS at diagnosis was statisti-
cally significantly different for these two groups, but not
other factors, including the serum calcium level and the
ISS-determined disease stage (Table 3).
Discussion
Treatment strategies for NDMM have gone through
major changes during the past decade. At the timing of
Table 2 Relationships of patients’ background, laboratory data and
long-term survival
OS TNT
Median (month) p value Median (month) p value
Age (years old)
\75 63.2 0.033 20 0.25
C75 48.3 16
Gender
Male 46.7 0.603 20 0.851
Female NR 17
Performance status
0–1 63.2 0.025 20 0.008
C2 42.8 11
Paraprotein type
IgG 52.5 0.329 18 0.373
IgA 50.1 22
Others NR 15.5
ISS, disease stage
1 66.3 0.41 23 0.308
2 50.1 18
3 NR 16
b2 Microglobulin (mg/dL)
C3.5 63.2 0.824 20 0.333
\3.5 52.5 16
Creatinine (mg/dL)
C2.0 NR 0.219 55 0.157
\2.0 52.5 19
Hemoglobin (g/dL)
C10.0 54.4 0.305 20 0.569
\10.0 48.3 17
Serum calcium (mg/dL)
C11.0 18.8 0.005 11.5 0.025
\11.0 54.4 19
Albumin (mg/dL)
C3.5 66.3 0.206 20 0.468
\3.5 48.3 17
Bold values indicate statistically significant p values
NR not reached, OS overall survival, TNT time to next treatment
Value of ISS for NDMM in the era of new agents
123
writing in 2013, the combination chemotherapies incor-
porating MP and bortezomib or IMiDs are widely rec-
ognized as first-line treatments on the basis of the results
of large clinical trials which showed better response rates
and longer favorable outcomes for MP combined with
bortezomib and/or thalidomide [18, 19, 23–26]. How-
ever, physical conditions including complications, past
disease history and abnormalities of laboratory data are
usually more erratic in daily clinical practice settings as
compared with those of patients who are eligible for
well-designed clinical trials. For instance, the use of
bortezomib is not recommended for patients with pul-
monary diseases or neurologic symptoms, and the use of
IMiDs is not recommended for patients having throm-
botic episodes. In such cases, MP therapy remains one of
the options for first-line chemotherapy for transplant-
ineligible NDMM. Although this study was retrospective,
the response rate and TNT associated with MP therapy
in patients analyzed in this study are mostly comparable
with those observed in other clinical trials [11–21]. The
median OS and median TNT were 54.4 and 19.0 months,
respectively, indicating that the salvage therapies using
novel agents produced patients’ survival periods for
approximately 3.0 years following the loss of response to
MP, even in the context of the first-line MP therapy.
It is noteworthy that our study revealed that ISS is not
predictive for TNT or OS in this setting, although TNT
of patients with ISS 1 tended to be longer than that of
others. This suggests that salvage therapies using various
novel agents could overcome the negative impact of an
unfavorable ISS score. Previous studies by others have
also occasionally pointed out the loss of impact of ISS
on the long-term outcome of MM in the era of new
agents [27–29], supporting our results which indicate the
need for the development of more convincing prognostic
score. In contrast, our results revealed that the presence
of hypercalcemia at diagnosis was predictive for unfa-
vorable prognosis in the setting of MP as the first-line
therapy with the aid of salvage therapy using novel
agents. In our cohort, hypercalcemia over 11.0 mg/dL of
serum calcium was identified in only 8 of 131 patients
(6.1 %), suggesting that hypercalcemia can identify
rather minor population with unfavorable outcome even
with the salvage treatment by novel agents. Recent study
demonstrated the positive link between hypercalcemia
and ultra-high-risk MM patients those are characterized
by the presence of del(17p) chromosomal abnormality or
plasma cell leukemia [30, 31]. Although the underlying
mechanism for poor prognosis of the presence of
hypercalcemia remains unclear in our cohort, hypercal-
cemia at diagnosis might implicate the aggressive and
drug-resistant phenotype of MM.
The degree of response, especially CR, has shown a
strong relationship with the longer survival of MM
patients regardless of treatment type [32]. Since our
study also disclosed that the response to MP therapy was
directly associated with long-term outcome, we tried to
identify the factors which can predict the response to MP
therapy alone. In contrast to ISS disease staging, unfa-
vorable PS was significantly associated with poor
response to MP therapy. Unfavorable PS was signifi-
cantly associated with older age, but not associated with
the presence of bone lesions. The response to MP and
the long-term outcome for patients may, therefore, be
a bOS TNT
0 20 40 60 80
0.0
0.2
0.4
0.6
0.8
1.0
Months
Pro
babi
lity
ISS123
0 20 40 60 80
0.0
0.2
0.4
0.6
0.8
1.0
Months
Pro
babi
lity
ISS123
Fig. 3 Disease staging according to the International Staging System (ISS) does not faithfully predict the long-term outcome NDMM patients
treated with MP as the first-line strategy. OS (a) and TNT (b) according to disease stage determined with the ISS
J. Kuroda et al.
123
affected by the co-emergence of several factors associ-
ated with poor PS, such as various non-osseous mye-
loma-related/-unrelated organ tissue impairments which
accumulate along with aging.
Since this is a retrospective study, the limitations of this
study are lack of laboratory data, cytogenetic/molecular
data, and unbiased schedule and choice of treatment,
especially for salvage treatment. Nevertheless, the results
presented here suggest the need for the novel and more
sophisticated prognostic system, incorporating both bio-
markers and/or radiological findings directly associated
with myeloma biology, such as tumor size, cytogenetics,
genetics, epigenetic abnormalities, or immunologic profile
[1, 33–38], and scores for patients’ co-morbidity [29, 39,
40], which can more accurately predict the long-term
outcome NDMM patients in the era of new agents.
In conclusion, in the setting of the first-line MP therapy
with subsequent salvage therapy with novel agents,
hypercalcemia and unfavorable PS are predictive of a
shorter survival period, and PS associates with the degree
of response to MP, while the predictive value of ISS for OS
might be limited in the era of novel agents. This study
0 20 40 60 80
0.0
0.2
0.4
0.6
0.8
1.0
Months
Pro
babi
lity
CR + VGPRPR
0 20 40 60 80
0.0
0.2
0.4
0.6
0.8
1.0
Months
Pro
babi
lity
CRVGPRPRSDPD
0 20 40 60 80
0.0
0.2
0.4
0.6
0.8
1.0
Months
Pro
babi
lity
CR + VGPRPR
0 20 40 60 80
0.0
0.2
0.4
0.6
0.8
1.0
Months
Pro
babi
lity
CRVGPRPRSDPD
1 2 3
ISS
a
b c
d e
OSOS TNTTNT
PDSDPRVGPRCR
Fre
quen
cy
0.0
0.2
0.4
0.6
0.8
1.0Fig. 4 Response to MP and
survival. a Response to MP
therapy according to disease
stage determined with the ISS.
Attainment of better than VGPR
was significantly associated
with favorable OS (b) and TNT
(c) (Blue lines; CR plus VGPR,
Black lines; less than PR in
(b) and (c)) OS (d) and TNT
(e) in terms the best response.
(Blue lines; CR, Black lines;
VGPR, Green lines; PR,
Orange-colored lines; SD, Pink
lines; PD)
Value of ISS for NDMM in the era of new agents
123
suggests the need for the development of novel and gen-
eralized prognostic system for MM in the era of new
agents.
Acknowledgments We wish to thank Drs. M. Matsuda, T. Hamada,
T. Kida, T. Kohara, K. Miyamoto, M. Shindo, Y. Matsumura, Y.
Yoshii, Y. Adachi, H. Yagi, M. Iida, and all researchers of the KMF
for their scientific support.
Conflict of interest This work was partly supported by a research
fund from the Celgene Corporation (Summit, NJ).
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Table 3 Relationships between response to MP therapy and clinical
parameters
CR/VGPR PR/SD PD p value
CR/VGPR
vs. PD
Male (%) 41.7 45.1 62.5 0.650
Non-IgG type (%) 50.0 39.6 62.5 0.670
PS, C2 (%) 0.0 28.8 50.0 0.014
ISS, C2 (%) 75.0 73.9 37.5 0.167
Serum creatinine (mg/dL),
median
0.96 0.80 1.25 0.153
Serum calcium (mg/dL),
median
9.2 9.6 9.8 0.213
Serum albumin (mg/dL),
median
3.9 3.6 3.3 0.485
Serum b2-microglobulin
(mg/dL), median
2.9 3.8 3.4 0.847
Bone marrow myeloma
cells (%)
17.9 21.0 46.4 0.182
Any bone lesion (%) 63.6 58.6 71.4 0.714
Number of bone lesions,
C2 (%)
54.5 34.2 71.4 0.637
Extramedullary lesion (%) 0.0 9.0 25.0 0.183
Bold value indicates statistically significant p values
CR/VGPR complete response/very good partial response; PR/SD
partial response/stable disease; PD progressive disease
J. Kuroda et al.
123
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Value of ISS for NDMM in the era of new agents
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