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: junkuro@koto.kpu-m.ac.jp

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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