International Journal of Myeloma 10(2): 21–25, 2020
©Japanese Society of Myeloma

ORIGINAL

Impact of high serum lactate dehydrogenase in multiple myeloma in
upfront autologous stem cell transplantation in the era of new drugs:
A single institute experience
Saeko KUWAHARA-OTA, Yuji SHIMURA, Yoshimi MIZUNO, Tomoko TAKIMOTO-SHIMOMURA,
Yayoi MATSUMURA-KIMOTO, Kazuna TANBA, Taku TSUKAMOTO, Yoshiaki CHINEN,
Shinsuke MIZUTANI, Tsutomu KOBAYASHI, Shigeo HORIIKE and Junya KURODA
We retrospectively analyzed the clinical outcomes and prognostic factors of 26 newly-diagnosed multiple
myeloma (MM) patients treated with bortezomib (BTZ)-containing induction therapy prior to HDT/ASCT (BTZ
group). Twenty-six patients who were not treated with BTZ were used as a historical control (control group).
Compared with the historical controls, median progression-free survival (PFS) of the BTZ group was significantly
longer (48.5 M vs. 21.4 M), while the median overall survival (OS) was not (not achieved vs. 76.9 M). Both post-­
induction- and post-ASCT-response rates were significantly better in the BTZ group compared with the controls.
Multivariate analyses revealed that a high serum LDH level at diagnosis was associated with both shorter PFS and
OS. The introduction of new drugs before auto-SCT improved the clinical response and PFS but did not improve
OS. High LDH at diagnosis is an independent poor prognostic factor in the setting of HDT/ASCT even in the era of
new drugs.
Key words:

multiple myeloma, autologous stem cell transplantation, bortezomib

Introduction

therapy before HDC/ASCT is expected to produce longer­disease control after ASCT [3].

Multiple myeloma (MM) is a hematological malignancy that

The incorporation of bortezomib (BTZ) into the induction

is characterized by abnormal proliferation of clonal plasma

therapy has shown clinical benefit for MM patients in the set-

cells in bone marrow. While the treatment outcome of MM hasting of upfront HDC/ASCT [4]. BTZ-based regimens have been

been improved dramatically by the use of novel agents, i.e.,

used as second-line induction therapy, in case the treatment

proteasome inhibitors and immunomodulatory drugs (IMiDs),

response did not achieve a very good partial response (VGPR)

MM still remains difficult to treat and most patients eventually[5] following first-line conventional chemotherapeutic induc-

relapse. Induction chemotherapy, followed by high-dosetion, i.e., high-dose dexamethasone (DEX) or the combination

chemotherapy with autologous stem cell transplantationof vincristine, adriamycin (ADR) and DEX (VAD) from 2008 to(HDC/ASCT) as the first-line treatment, has shown promise in2011, while was utilized as the first-line induction therapy

prolonging progression-free survival (PFS) in newly diagnosed

since 2011 in our institute. To assess the clinical benefit of a

MM (NDMM) patients who are eligible for myeloablative HDC

novel agent-containing induction regimen, we retrospectively[1, 2]. The achievement of a deeper response by induction

analyzed the treatment outcomes and prognostic factors of
NDMM who received BTZ-containing induction regimen fol-

Received May 7, 2020, accepted August 22, 2020
Division of Hematology and Oncology, Department of Medicine,
Kyoto Prefectural University of Medicine
Corresponding author: Yuji SHIMURADivision of Hematology and Oncology, Department of Medicine,
Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku,
Kyoto 602-8566, Japan
E-mail: yshimura@koto.kpu-m.ac.jp

lowed by HDT/ASCT in our institute.

Patients and Therapies
A total of 26 NDMM patients who were diagnosed andtreated in our institute from January 2008 to May 2017 wereanalyzed retrospectively. BTZ and DEX regimen (BD: BTZ (1.3
mg/m2/day) on days 1, 4, 8 and 11, and DEX (20 mg/day) on

International Journal of Myeloma

vol. 10 no. 2 (2020)

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KUWAHARA-OTA et al.

days 1, 2, 4, 5, 8, 9, 11 and 12, every 21 days) were mainly usedage, performance status (PS), paraprotein types, disease stage

from Jan 2008 to 2012, as the second-line or the first-line

according to the International Staging System (ISS) [8], serum

induction therapy. Since 2013, cyclophosphamide (CY) was

calcium, creatinine and lactate dehydrogenase (LDH) levels,

added to the induction regimen (CBD: CY (300 mg mg/m2/day)hemoglobin levels, bone lesions, and the proportion of bone2

on days 1, 8, 15 and 22, BTZ (1.3 mg/m /day) on days 1, 8, 15

marrow myeloma cells before therapy. Since chromosomaland 22, and DEX (40 mg/day) on days 1, 8, 15, and 22, every 35

abnormality (CA) was not routinely tested in all patients, datadays). Fourteen and 11 patients received BD and CBD, respec-

regarding high risk CA were excluded in subsequent analysis.

tively. One patient received both regimens (BTZ group). As a

The response rates before/after HDC/ASCT are also shown inhistorical control group, 26 patients treated with conventional

Table 1. Patients receiving the BTZ-containing regimen showed

induction therapy from 2002 to 2010 were analyzed (control

superior clinical responses compared with the control group;group, those included all patients who had received ASCTwith the rate of better than VGPR before HDC/ASCT to 62%

except clincal trials or those who received subsequent allo-

compared with 23% in the historical control group. Similarly,

geneic transplantation). Principally, patients received four

the rates of better than VGPR after HDC/ASCT in the BTZ groupcycles of induction therapy and then proceeded to peripheral

was increased to 86%, which was still superior to control

blood hematopoietic stem cell collection. Intermediate doses

group (43%). All patients were successfully engrafted and noof cyclophosphamide (1.5–4 g/m2) and granulocyte colony

therapy-related deaths were observed within two months

stimulating factor (G-CSF) were utilized in the collection [6].

from transplantation in either group.

Sufficient amounts of CD34 positive cells (range, 2.04–98.7 ×
6With median follow-up periods from the day of transplanta-

10 cells/kg) were harvested from all patients. Subsequently,

tion of 48.3 months (M) in the BTZ group and 83.2 M in thepatients received HDC with high-dose melphalan (100control group, the median PFS of the BTZ-regimen group was

2

mg/m /day) on days –3 and –2, followed by ASCT on day 0,

significantly longer than that of the control group (50.0 M vs.

and G-CSF was continued from day 1 to the day of neutrophil

21.4 M; P = 0.01), while the median OS was not statistically dif-2

engraftment. BTZ (1.0 mg/m on days –6, –3, 1, and 4) was

ferent between the two group (88.0 M in the BTZ group vs.

combined with high dose melphalan in HDC in some­

76.9 M in the control group; P = 0.94) (Fig. 1). Those whopatients. Levofloxacin, fluconazole and acyclovir were used

received maintenance therapy was significantly higher in BTZ-

prophylactically against infection. The treatment responsegroup, but PFS or OS was not significantly different between

was evaluated according to the criteria established by thepatients who received or not received maintenance therapy

International Myeloma Working Group [5]. Maintenance ther-(data not shown).

apy with low dose lenalidomide was administered in caseWe next investigated the prognostic factors that were

the treatment response rate after ASCT did not reach theassociated with the 26 myeloma patients treated with the

VGPR. This study was conducted in accordance with the

BTZ-containing regimen followed by HDC/ASCT. Univariate

ethical principles of the Declaration of Helsinki, and was­analysis revealed that a higher proportion of bone marrowapproved by our institutional review boards.

myeloma cells at diagnosis (≥60%) was associated with shorter
OS (47.8 M vs. not reached, P = 0.03) and that a high serum

Statistical analysis

LDH level at diagnosis was associated with both shorter PFS

All analyses were performed with EZR version 1.36 [7]. Overall(12.5 M vs. 64.3 M, P < 0.01) and shorter OS (63.1 M vs. notsurvival (OS) and PFS were calculated using the Kaplan-Meierreached, P = 0.02) (Table 2). Multivariate analyses revealed thatmethod, and results were compared using log-rank statistics

older age was significantly associated with shorter OS (HR,for univariate analysis and Cox proportional hazards model

7.07; 95% CI, 1.03 to 48.3; P = 0.04), while high serum LDH level

for multivariate analysis. Mann–Whitney U or Student’s t-tests

at diagnosis was associated with both shorter PFS (HR, 6.31;

and Fisher exact test were used for comparison of continuous

95% CI, 1.42 to 28.0; P = 0.01) and OS (HR, 15.8; 95% CI, 1.52 toor qualitative variables, respectively. P-values below 0.05 were163; P = 0.02) (Table 2). In this study, ISS was not related withregarded as significant. Missing data were excluded fromeither OS or PFS.

analysis.

Discussion
Results
Wherein, we described the clinical outcome and prognostic
The patients’ characteristics are summarized in Table 1. No

factors of NDMM treated with BTZ containing induction ther-statistically significant differences were observed between the

apy followed by HDC/ASCT in our institute. Several studies

BTZ group and the historical control group, in terms of gender,

have reported the superiority of the BTZ-containing regimen

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ASCT with BTZ containing induction

Table 1. Patients’ characteristics and disease status at diagnosis and treatment response to the induction therapy
BTZ group
Sex, nMale/Female

Type of M protein, nLight chain, nISS, nP value

12/14

13/13

0.79

56.5 (37–68)

57.5 (40–68)

0.78

0–1

23

21

≥2

3

0

Age, median (range)
Performance status, nControl group

Missing

0

5

IgG

13

11

IgA

12

15

Missing

1

0

κ

15

13

λ

10

10

Missing

1

3

1

11

7

2

8

9

3

7

7

Missing

0.29

0.51

0.81

0.78

0

3

Ca (mg/dl) median (range)

10.0 (8.5–13.1)

9.4 (8–12.3)

0.46

Cre (mg/dl) median (range)

0.90 (0.34–4.77)

1.2 (0.45–4.59)

0.69

Hb (g/dl) median (range)

9.9 (5.6–15.8)

10.1 (4.3–17.6)

0.90

Bone lesions, n

20/6

22/4

0.73

LDH (IU/l) median (range)

197 (114–350)

199.5 (124–323)

0.74

BM myeloma cell ratio median (range)

40.3 (8–97.6)

28.1 (5–60.8)

0.08

sCR, CR

2

0

VGPR

14

6

PR

10

12

Treatment response before ASCT, nTreatment response after ASCT, n

High-risk chromosomal abnormality, nMaintenance therapy, n

+/–

SD

0

6

Missing02

sCR, CR

12

5

VGPR

8

6

PR

5

10

SD, PD1

5

del(17p)

1/11

1/6

t(4;14)

7/24

2/11

t(14;16)

0/9

0/6

+/–

11/15

3/23

<0.01

0.06

0.03

Abbreviations. ASCT: autologous stem cell transplantation, BM: bone marrow, BTZ: bortezomib, Ca: serum calcium, Cre: serum
creatinine, Hb: hemoglobin, Ig: immunoglobulin, ISS: International Staging System, LDH: serum lactate dehydrogenase, sCR:
stringent complete response, CR: complete response, VGPR: very good partial response, PR: partial response, SD: stable disease.

as the induction strategy for NDMM patients who are candi-

Consistent with previous studies, in our current cohort,

dates for upfront HDC/ASCT. In the IFM 2005-01 study, the BD

incorporation of BTZ in induction therapy was shown to sig-

regimen significantly improved the response rate duringnificantly improve the treatment response, both before andpost-induction therapy and resulted in a trend towards PFS

after ASCT, and the median PFS of the BTZ group was sig­

prolongation compared with the conventional VAD regimen

nificantly prolonged compared with that of control group.

[4]. Moreover, meta-analysis of the BTZ-based versus the non-

However, the median OS did not improve significantly in the

BTZ-based induction regimens showed that the use of BTZ-BTZ group, which was likely due to the effective salvage

based induction was associated with significant improvements­chemotherapies implemented in the control group between

in the clinical response and survival in the setting of upfront

2002 and 2010 [10–13].

HDC/ASCT in transplant-eligible NDMM [9].

Despite the improvement of treatment outcome by induc-International Journal of Myeloma

vol. 10 no. 2 (2020)

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KUWAHARA-OTA et al.

Figure 1. Survival period after autologous stem cell transplantation (ASCT). a) Progression-free survival (PFS) curves and b) Overall survival (OS)curves for the bortezomib (BTZ) and control groups.

Table 2. Univariate and multivariate analysis of factors associated with OS and PFS in MM patients in BTZ group
Univariate analysis
OS (median, M)

P value

PFS (median, M)

P valueAge (≥61)

47.8 vs. NR

0.09

28.2 vs. 64.3

0.05

Sex (Male)

NR vs. 63.1

0.33

64.3 vs. 28.2

0.56

Performance status (≥2)

88.0 vs. NR

0.19

28.2 vs. 64.3

0.78

ISS (≥2)

NR vs. 88.0

0.58

48.5 vs. 49.9

0.51

Response before ASCT (≥VGPR)

NR vs. 63.1

0.44

48.5 vs. 49.9

0.98

Response after ASCT (≥CR)

NR vs. 88.0

0.89

48.5 vs. 49.9

0.82

BM myeloma cell ratio (≥60%)

47.8 vs. NR

0.03

18.8 vs. 49.9

0.17

Presence of bone lesions

NR vs. 88.0

0.37

48.5 vs. 88.4

0.61

Hypercalcemia (≥11mg/dl)

55.4 vs. NR

0.13

25.8 vs. 49.9

0.89

Renal dysfunction (Cre ≥1.0mg/dl)

53.3 vs. NR

0.11

25.8 vs. 49.9

0.41

Anemia (Hb < 10g/dl)

63.1 vs. NR

0.36

28.2 vs. 49.9

0.78High LDH level (≥250 U/L)

63.1 vs. NR

0.02

12.5 vs. 64.3

<0.01

Maintenance (+)

NR vs. 88.0

0.41

49.9 vs. 48.5

0.67

Multivariate analysis

OS

PFS

Hazard ratio (95% CI)

P valueAge (≥61)

7.07 (1.03–48.3)

0.04

BM MM cell ratio (≥60%)

6.92 (0.87–55.3)

0.07

High LDH level (≥250 U/L)

15.8 (1.52–163)

0.02

Age (≥61)

2.45 (0.72–8.37)

0.15High LDH level (≥250 U/L)

6.31 (1.42–28.0)

0.01

Abbreviations. OS: overall survival, PFS: progression free survival, MM: multiple myeloma, BTZ, bortezomib, ISS: international
staging system, ASCT: autologous stem cell transplantation, BM: bone marrow, Cre: serum creatinine, Hb: hemoglobin, LDH:
serum lactate dehydrogenase, M: months, NR: not reached.

tion therapy with novel drugs followed by HDC/ASCT, occa-

treated with the BTZ-containing induction regimen followed

sional early relapse and/or progression after HDC/ASCT stillby HDC/ASCT. High serum LDH is suggested to reflect theremains a critical problem. Among several factors that haveaggressiveness of the disease and high tumor burden in MM

been reported as poor prognostic factors in MM, this study

and, indeed, has been incorporated as one of the risk factors

revealed that high LDH level at diagnosis was an independent

in the Revised International Staging System (R-ISS) [14, 15].

poor prognostic factor for PFS and OS in NDMM patients

This identifies an unmet need for the development of risk-­

24

International Journal of Myeloma

vol. 10 no. 2 (2020)

ASCT with BTZ containing induction

stratified therapeutic approach, i.e., more intensive induction,
conditioning and/or post-ASCT treatments, for patients withhigh serum LDH level at diagnosis. Furthermore, it is expected

4.

that elucidating the molecular features of MM patients withhigh serum LDH will lead to the development of future­molecular targeted therapeutics.
In conclusion, the introduction of new drugs before ASCT
improved the clinical response and PFS but did not improve5.

the OS. High serum LDH still remains as one of the poor prognostic factors, even in the era of novel agents in the setting of
upfront HDC/ASCT, and the development of more effective

6.

therapeutic strategies, based on the proper identification ofhigh-risk patients at diagnosis is necessary to improve theoverall clinical outcome of MM.

7.

Conflict of Interest
8.

J.K. has received research funding from Celgene, Kyowa
Kirin, Chugai Pharmaceutical, Ono Pharmaceutical, Sanofi,
Eisai, Bristol-Myers Squibb, Sysmex, Astellas Pharma, Pfizer,

9.

Sumitomo Dainippon Pharma, Nippon Shinyaku, MSD,
Fujimoto Pharmaceutical and Otsuka Pharmaceutical, hasreceived honoraria from Janssen Pharmaceutical K.K., Celgene
Corporation, Kyowa Kirin, Chugai Pharmaceutical, Ono Pharmaceutical, Sanofi, Eisai, Bristol-Myers Squibb, Astellas Pharma,

10.

Pfizer, Nippon Shinyaku, Sumitomo Dainippon Pharma,
Fujimoto Pharmaceutical, AbbVie and Otsuka Pharmaceutical,
and is a consultant for Janssen Pharmaceutical K.K., Celgene,

11.

Bristol-Myers Squibb, Sanofi and AbbVie. T.K. has received
research funding from MSD, and has received honoraria from

12.

Chugai Pharmaceutical, Ono Pharmaceutical, Eisai, and Nippon
Shinyaku.

13.

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