International Journal of Myeloma 5(3): 15–22, 2015
©日本骨髄腫学会

ORIGINAL

Efficacy and safety of bortezomib-containing induction
chemotherapy for autologous stem cell transplantation-eligible
Japanese multiple myeloma patients—A phase 2 multicenter trial—
Daisuke KUDO1, Kazuteru OHASHI2, Takuya KOMENO3, Yuichi NAKAMURA4,
Atsushi SHINAGAWA1, Chikashi YOSHIDA3, Yukitaka KATSURA3, Ikuyo OTA3, Kazuhiko KAKIHANA2,
Takeshi KOBAYASHI2, Nobutaka KAWAI5, Atsushi KATO6, Ayako ARAI7, Koh YAMAMOTO8,
Shigeo TOYOTA9, Takashi KUMAGAI10, Akira OHWADA11, Toru MIKI12, Mitsuo HORI13,
Yasushi OKOSHI13,14, Hiroshi KOJIMA14,15 and Hisashi SAKAMAKI2;
on behalf of the Ochanomizu Hematology Study GroupA phase II multicenter trial was conducted to analyze the efficacy and safety of a bortezomib-containing regimen
for induction prior to autologous stem cell transplantation (ASCT) in newly-diagnosed multiple myeloma Japanesepatients under the age of 65. The induction regimen consisted of one cycle of vincristine-doxorubicin-dexamethasone
followed by 3 cycles of twice-weekly bortezomib-dexamethasone (BD). Responding patients underwent stem cell
harvesting and ASCT. The primary endpoint was the post-induction response rate (RR). Forty-one patients wereenrolled from September 2009 to December 2012. Post-induction RR was 85.4% including 17.1% CR, 4.9% nCR, and34.1% VGPR. Three-year progression-free and overall survival were 51.9% and 90.3%, respectively. During induction,
grade ≥3 hematologic adverse events (AEs) were frequent, of which infection was the most prevalent: 2 events
during VAD and 7 events during BD. A total of 8 patients (19.5%) dropped out during induction due to AEs. Furthermore, 15 patients dropped out prior to ASCT, 10 of whom were due to AEs. Only 26 patients (63.4%) proceeded to
ASCT, resulting in a relatively low RR after ASCT (58.5%, including 14.6% CR, 17.1% nCR, and 12.2% VGPR). Cliniciansmust be wary of possible serious AEs, both during and after BD induction, when applied to Japanese patients.
Key words:

multiple myeloma, induction chemotherapy, bortezomib, autologous stem cell transplantation,
adverse events

Received: April 2, 2015, accepted: June 4, 2015
1
Department of Hematology, Hitachi General Hospital
2
Division of Hematology, Tokyo Metropolitan Komagome Hospital3
Department of Hematology, National Hospital Organization Mito
Medical Center
4
Department of Hematology, Saitama Medical University Hospital
5
Department of Hemato-oncology, Saitama International Medical
Center, Saitama Medical University
6
Department of Hematology, Japanese Red Cross Musashino Hospital
7
Department of Hematology, Tokyo Medical and Dental University
Hospital
8
Department of Hematology, Yokohama City Minato Red Cross
Hospital
9
Department of Hematology, Yokosuka Kyosai Hospital
10
Department of Hematology, Ohme Municipal General Hospital

11

Department of Internal Medicine, Tokyo Metropolitan Bokutoh
Hospital
12
Department of Internal Medicine, Flowers & Forest Tokyo Hospital
13
Department of Hematology, Ibaraki Prefectural Central Hospital
14
Department of Medical Oncology, Ibaraki Prefectural Central
Hospital
15
Ibaraki Clinical Education and Training Center, University of Tsukuba
Hospital
Corresponding author: Hiroshi KOJIMA, M.D., Ph.D.
Ibaraki Clinical Education and Training Center, University of Tsukuba
Hospital, 6528 Koibuchi, Kasama, Ibaraki 309-1793, Japan
TEL: 81-296-77-1121, FAX: 81-296-77-2886
E-mail: h-kojima@chubyoin.pref.ibaraki.jp

International Journal of Myeloma

vol. 5 no. 3 (2015)

15

KUDO et al.

Introductionin Japan, the present study adopted a VAD/BD regimen consisting of one cycle of VAD followed by three cycles of BD for

Despite the recent emergence of novel drugs, multiple

induction chemotherapy. The present study was thus designed

myeloma (MM) remains an incurable plasma cell neoplasm. It

to clarify the feasibility of introducing a bortezomib-containing

is now widely accepted that high-dose therapy (HDT) com-

regimen for induction therapy before ASCT as a daily generalbined with ASCT improves RR, progression-free survival (PFS),

practice in Japanese patients.

and overall survival (OS) in patients with newly diagnosed MM

Patients and Methods(NDMM) under the age of 65. Indeed, several randomized trials
demonstrated the superiority of HDT over standard-dose therapy in this population of patients. Historically, the vincristine-

Patients

doxorubicin-dexamethasone (VAD) regimen has long been a

Patients were eligible if they had NDMM defined by thestandard for induction therapy, due to its non-toxicity to nor-International Myeloma Working Group (IMWG) criteria 12), Duriemal bone marrow stem cells, allowing substantial stem cell

& Salmon stage II–III disease, and were aged 15–65 years. Key

mobilization. Moreover, the VAD regimen achieves reasonable

inclusion criteria were Eastern Cooperative Oncology Group

1–3). A recent randomized trial with the VAD regimen(ECOG) performance status (PS) of 0–2 (patients with PS 3-4

as a control arm reported that VAD achieves a RR of 52%,

due to myeloma pain were eligible), no previous anti-myeloma

including 14% very good PR (VGPR) and 8% complete

therapy, and adequate hepatic (bilirubin, AST, ALT < 2x normal

response (CR) 4). Meta-analyses of the HDT strategy further

upper limit), hematologic (white blood cell counts ≥ 3 × 109/L,

revealed that maximal response after completion of the induc-absolute neutrophil counts ≥ 1.5 × 109/L, hemoglobin ≥ 8.0

responses

5)tion is closely related to long-term outcome , suggesting theg/dl, platelet counts ≥ 100 × 109/L), cardiac (EF ≥ 50%), pulmo-

relevance of achieving deeper response in the induction phasenary (FVC, FEV1.0, DLCO ≥ 50%, SaO2 ≥ 90%), and renal (serum

before ASCT. Based on this notion, the majority of recent

creatinine ≤ 4 mg/dl) function. RBC transfusion or usage of­clinical studies have included novel drugs instead of VAD inrecombinant human erythropoietin prior to enrollment was

the induction phase. One of these, bortezomib, is a reversible

allowed. Patients with ≥ grade 2 PN or neuropathic pain were

proteasome inhibitor which binds directly to the enzymatic

excluded from the study.

complex of the proteasome, blocking its chymotrypsin-like
activity and thus inhibiting the degradation of multiple pro-Study design

teins. Proteasome inhibition results in the disruption of various

This study was conducted as a phase II single-arm open-

intracellular signaling pathways, leading to cell cycle arrest

label multicenter trial of 11 institutions in Japan. The protocol

and apoptosis in myeloma cells, and inhibition of surrounding

was approved by the institutional review board of each institu-

angiogenesis

6,7)

.

tion. All patients provided written informed consent. Patients

Considerable data have been accumulated demonstratingwere enrolled from September 2009 to December 2012, andthe significant clinical activity of bortezomib both as a conven-received induction chemotherapy with one cycle of VAD fol-tional chemotherapy agent 8) and as an induction chemother-

lowed by 3 cycles of twice-weekly BD (VAD/BD). The VAD regi-

9)

apy agent prior to HDT . In the IFM phase III trial evaluating

men consisted of a 28-day cycle of vincristine (0.4 mg/day, day

the efficacy of a BD regimen as an induction agent in compari-1–4) and doxorubicin (9 mg/m2/day, day 1–4) by continuous

son with VAD for ASCT-eligible NDMM, overall RR achieving at

intravenous (IV) infusion plus dexamethasone (40 mg, IV, day

least PR was 78.5%, including 37.7% of VGPR and 14.8% of

1–4). BD consisted of 21-day cycles of bortezomib (1.3 mg/m2,

CR or near CR (nCR), after 4 cycles 10). Superiority of BD overIV, day 1, 4, 8, and 11) plus dexamethasone (40 mg, IV or orally,

VAD in terms of event-free survival (EFS) and OS was reported

day 1, 2, 4, 5, 8, 9, 11, and 12). Anti-varicella-zoster virus (VZV)

to persist even after ASCT. In this IFM trial, total incidence ofprophylaxis was recommended during the BD induction.

severe AEs was comparable between the VAD and BD groups,

Approximately 4 weeks after the completion of the induction

although peripheral neuropathy (PN) was more prevalent intreatment, stem cells were mobilized by administrating cyclo-

the BD group. A meta-analysis integrating four phase III trials,

phosphamide (2 g/m2, IV, day 1, 2) followed by lenograstim

including the IFM trial, confirmed the superiority of bortezomib-(10 μg/kg/day), starting the day the neutrophil count fell underbased induction chemotherapy with acceptable toxicity 11).

1 × 109/L. The target yield of stem cells was 4 × 106 CD34-

However, in Japan, little has been reported on the efficacy

positive­cells/kg. Conditioning for ASCT was performed using

and safety of introducing bortezomib in the induction phasemelphalan (200 mg/m2, IV, day –2). The second transplanta-

for ASCT-eligible NDMM. Because bortezomib had not beention was performed by physician’s decision if VGPR was not

approved for the treatment of NDMM until September 2009

achieved after the first transplantation. Maintenance therapy

16International Journal of Myeloma

vol. 5 no. 3 (2015)

BTZ as induction before ASCT for Japanese MM

Results

was not prescribed by the protocol.
Treatment with BD was prolonged with observation ofgrade 4 hematologic or grade ≥3 non-hematologic toxicity,

Patient characteristics

excluding PN, until its recovery to ≤ grade 2. Management of

Characteristics of patients are summarized in Table 1. Forty-

PN was defined as shown below. After recovery from toxicity,

one patients were enrolled in this study. Median age was 59

treatment was restarted after stepwise dose-reduction ofyears ranging from 40 to 65 years, and the male to female ratio

the responsible drug as follows: bortezomib, 1.3, 1.0, andwas 23:18. Clinical stages were stages II and III by the Durie &0.7 mg/m2; and dexamethasone, 40, 30, and 23 mg/body.

Salmon system in 13 and 28 patients, respectively (n = 41), and­Further dose reduction was not permitted. When the toxicity

stages I, II, and III by the International Staging System (ISS) in

was unable to be reduced to under grade 3 after 2 weeks’12, 17, and 9 patients, respectively (n = 38). Three patients­prolongation, or when grade 4 hematologic or grade ≥3 non-were excluded from the ISS analysis due to the unavailability

hematologic ­toxicity manifested even at the lowest dose level,of serum levels of β2 microglobulin. Chromosomal analysis of

the patient was withdrawn from the trial. Bortezomib-inducedbone marrow cells was performed in all patients; however, thePN was managed following the established guideline exactly 13):

results were not available in 2 patients due to poor cell divi-

grade 1, no dose-reduction; grade 1 with pain or grade 2,

sion. Among 39 available patients, 32 showed normal karyo-­stepwise dose-reduction (1.3, 1.0, and 0.7 mg/m2); grade 2type, and 7 showed abnormal karyotype, including 5 patientswith pain or grade 3, resuming the treatment at a dose of 0.7

with hyperdiploidy and 2 patients with non-hyperdiploidy

mg/m2 for a once-week schedule after the recovery of PN lesskaryotypes. Deletion 13 was observed in 3 patients, and 2 ofthan grade 2; and grade 4, withdrawal from the study.

them showed hyperdiploid karyotypes. Because the use ofThis study was registered at the University Hospital Medical
Information Network (UMIN) Clinical Trials Registry (http://
www.umin.ac.jp/ctr/) as UMIN000002611.
Endpoints and assessment
The primary endpoint of this study was post-induction RR
achieving at least PR. Secondary endpoints were OS, PFS, andsafety of the VAD/BD induction chemotherapy. Therapeutic
response was evaluated at post-induction and post-first ASCT
according to the International Myeloma Working Group(IMWG) uniform response criteria 14). nCR was defined as a condition achieving CR but with positive immunofixation test 15).
AEs were evaluated according to NCI-CTC version 3.0 criteria.
Statistical analyses
The present study was designed by employing a binominal
distribution with a one-sided type I error of 0.05 and statisticalpower of 80%. Post-induction RR was initially estimated to be
80% due to a previous report stating RR with VAD was 63% 16).
All patients meeting the eligibility criteria who had started
the first cycle of chemotherapy were evaluated for toxicity,
response, and survival. The Kaplan-Meier method was used toestimate the distributions of PFS and OS. Times of observation
were censored on June 30, 2014. Influence of each parameteron the achievement of post-induction RR was evaluated byStudent’s t-test or Fisher’s exact test. Multivariate analysis was
performed by a logistic model regression. A calculated p valueof less than 0.05 was interpreted to indicate statistical significance. All analyses were performed with the STATA13 software(StataCorp LP, TX, USA).

Table 1.
Characteristic

Characteristics of patients
No. of Patients (n = 41)%

Age, years
Median (Range)

59 (40–65)

Sex
Male
Female

23
18

56
44

DS Stage
II
III

13
28

32
68

ISS Stage
I
II
III
NA

12
17
9
3

29
41
22
7

PS
0–1
2–4

30
11

73
27

Immunoglobulin-type
IgG
IgA
IgD
BJP

23
9
3
6

56
22
7
15

Karyotype
NormalHyperdiploidy
non-HyperdiploidyNAdel(13)

32
5
2
2
3

78
12
5
5
7

DS, Durie & Salmon; ISS, International Staging System; PS, performancestatus; NA, not available.
Chromosomal analysis was performed by G-banding.

International Journal of Myeloma

vol. 5 no. 3 (2015)17

KUDO et al.

Table 2. Therapeutic response
Induction
Response

CR
nCR
VGPR
PR
≥PR
SD
PD
Not evaluable

ITT(n = 41)

1st ASCT
ITT(n = 41)

Per Protocol(n = 26)

No.

%

No.

%

%

7
2
14
12
35
3
1
2

17.1
4.9
34.1
29.3
85.4
7.3
2.4
4.9

6
7
5
6
24
1
0
1

14.6
17.1
12.2
14.6
58.5
2.4
0.0
2.4

23.1
26.9
19.2
23.1
92.3
3.8
0.0
3.9

ITT, intention to treat; ASCT, autologous stem cell transplantation.

scribed by the protocol, 17 patients received maintenancetherapy, 9 with thalidomide and 8 with lenalidomide.
Therapeutic response
Results of the response to treatment are summarized inTable 2. Post-induction RR was 85.4% with 17.1% CR, 4.9% nCR,
and 34.1% VGPR by intention-to-treat (ITT) analysis. Univariate
analysis identified pre-treatment level of serum albumin as asignificant prognostic factor that positively influences postinduction achievement of ≥PR (p = 0.027) (Table 3). However,
Figure 1. Flow diagram of patients enrolled in the trial.

this was not validated by multivariate analysis (p = 0.201). RR
after the first ASCT was 58.5% with 14.6% CR, 17.1% nCR, and12.2% VGPR by ITT analysis, and 92.3% with 23.1% CR, 26.9%
nCR, and 19.2% VGPR by per-protocol analysis. Although the­fluorescent in situ hybridization (FISH) analysis was not manda-

second ASCT was performed in 3 patients, none of them

tory in this study, its usage was dependent on each physician’sachieved upgraded response. Efficacy of maintenance therapy

decision. t(4;14) was observed in 1 out of 14 analyzed patients,

was evaluated in 12 out of 17 patients excluding 4 patientsdel(17p) in 0 out of 5 patients, t(14;16) in 0 out of 2 patients,

who achieved CR after ASCT and 1 patient whose data wereand del(13) in 7 out of 13 patients.

unavailable. Among these 12 patients, 5 patients achieved
upgraded response.

Patient disposition
The flowchart of patient disposition is shown in Figure 1.

Progression-free and overall survival

Among 41 enrolled patients, one patient dropped out during

The median follow-up was 712 days. PFS and OS are shown

VAD because of an AE. Forty patients (97.6%) entered thein Figure 2. In total, 14 out of 41 patients experienced either

induction phase with BD, and 30 patients (73.2%) completed 3

disease progression (11 patients) or death (3 patients) during

cycles. A total of 10 patients dropped out during BD, 7 due tothe follow-up period. PFS at 1, 2, and 3 years (95% confidenceAEs, 2 due to treatment failure, and 1 due to agreement with-interval) were 84.5% (68.8–92.7), 67.5% (49.6–80.2), and 51.9%

drawal. Collectively, the drop-out rate due to AEs during the(27.1–72.0), respectively. OS at 1, 2, and 3 years were 97.4%

VAD/BD induction phase was 19.5% (8/41). Peripheral blood(83.2–99.6), 90.3% (72.5–96.8), and 90.3% (72.5–96.8), respec-

stem cell harvesting (PBSCH) and the first ASCT were per-tively. Median PFS and OS have not yet been reached.

formed in 30 (73.2%) and 26 (63.4%) of the 41 patients, respectively. During PBSCH, 4 patients dropped out: 2 due to AEs,

Safetyone due to poor mobilization, and one due to protocol

The safety profile during VAD (n = 41) and BD (n = 40) are­violation. The second ASCT was performed in 3 out of the 26

summarized in Table 4. Grade ≥3 hematologic AEs were fre-patients who completed the first ASCT. Although not pre-quently observed. In particular, the incidence of cytopenia was

18

International Journal of Myeloma

vol. 5 no. 3 (2015)

BTZ as induction before ASCT for Japanese MM

Table 3.

Factors influencing therapeutic outcome

Univariate analysis
Variables
Age, mean ± SD
Sex
Male
FemalePS
0–1
2–4
Alb, mean ± SD (g/dl)
β2MG, mean ± SD (mg/l)

Multivariate analysis

≥PR

<PR

(n = 35)(n = 6)57.3 ± 6.0

p value

Odds Ratio

95% CI

p value

56.7 ± 5.2

0.814

0.95

0.74–1.22

0.705

19
16

4
2

0.679

1.5

0.05–44.7

0.814

8
27
3.4 ± 0.7
4.8 ± 3.433
2.7 ± 0.5
3.6 ± 1.8

0.316

0.53

0.34–8.46

0.656

0.027
0.503

4.75
1.47

0.43–52.0
0.65–3.34

0.201
0.357

Alb, albumin; β2MG, β2-microglobulin.

Figure 2. Progression-free survival and overall survival. Kaplan-Meier analysis of progression-free survival (A) and overall survival (B) in the ITT
population.

high, with 26 events (19 out of 40 patients) during VAD and 13

encephalopathy syndrome, cytomegalovirus (CMV) infection,

events (11 out of 39 patients) during BD documented. How-

diarrhea, and pneumonia). Furthermore, 2 patients dropped

ever, grade 4 cytopenia rarely occurred during induction; onlyout during PBSCH (one due to pneumonia and one due to

1 event of anemia during VAD and 3 events of thrombocyto-

allergic reaction to cyclophosphamide).

penia during BD were documented. For infections, grade ≥3

Overall, 3 patients died during the study period. Twoevents were frequent; 2 events of sepsis during VAD and 7

patients died after the first ASCT due to tumor progression,

events of infection, including 4 of sepsis, 2 of bacterial pneu-

and one patient died during the first ASCT due to bacterialmonia, and 1 of VZV reactivation in a patient who didn’t

pneumonia.

receive anti-VZV prophylaxis, during BD. On the other hand,incidence of grade ≥3 non-hematologic AEs was relatively low

Discussion

throughout the induction. Among non-hematologic AEs, neuropathy was documented in 12.2% of patients during VAD and

In the present study, we analyzed the efficacy and safety of

27.5% of patients during BD. However, grade ≥3 neuropathy

a bortezomib-containing regimen for use as induction prior to

was rarely experienced: no patients during VAD and 2 patients

ASCT in Japanese patients. Because the use of bortezomib had(one PN and one orthostatic hypotension) during BD were

not been approved as a first-line therapy in Japan at the

documented.

time of the study’s commencement, a VAD/BD regimen was

One patient dropped out during VAD due to seizures, andadopted for use in the present study instead of BD for induc-seven patients during BD (one each due to VZV reactivation,tion. Thus, the present study was conducted for its use as aorthostatic hypotension, liver dysfunction, reversible posterior

daily medical practice, according to the Japanese health ser-International Journal of Myeloma

vol. 5 no. 3 (2015)19

KUDO et al.

Table 4.

Safety profile during induction

VAD (n = 40)

BD (n = 39)

Grade 3

Grade 4

Grade 3

Grade 4

Hematologic AEs

No.

%

No.

%

No.

%

No.

%

AnemiaLeukopenia
Thrombocytopenia
Infection
SepsisPneumonia
VZV reactivation

10
13
2
2
2
0
0

25
32.5
5
5
5
0
0

1
0
0
0
0
0
0

2.5
0
0
0
0
0
0

8
1
1
7
4
2
1

20.5
2.6
2.6
17.9
10.3
5.1
2.6

0
0
3
0
0
0
0

0
0
7.7
0
0
0
0

VAD (n = 41)

BD (n = 40)

Grade 3

Grade 4

Grade 3

Grade 4

Non-Hematologic AEs

No.

%

No.

%

No.

%

No.

%

Neuropathy
Peripheral neuropathy
Orthostatic hypotension
Fatigue
Anorexia
Constipation
Glucose intolerance
Liver dysfunction
Seizure

0
0
0
0
0
0
1
0
1

0
0
0
0
0
0
2.4
0
2.4

0
0
0
0
0
0
1
1
0

0
0
0
0
0
0
2.4
2.4
0

2
1
1
1
1
1
0
0
1

5
2.5
2.5
2.5
2.5
2.5
0
0
2.5

0
0
0
0
0
0
0
1
0

0
0
0
0
0
0
0
2.5
0

VAD (n = 41)

BD (n = 40)

Neuropathy

No.

%

No.

%

Grade 1
2
3
4

5
0
0
0

12.2
0
0
0

4
5
2
0

10
12.5
5
0

AEs, adverse events; VZV, varicella-zoster virus.

vice system. We observed that post-induction RR in Japanese

However, contrary to the favorable therapeutic outcome

patients was found to be comparable with that of preceding

achieved by the VAD/BD induction regimen, post-ASCT RR wastrials performed in foreign countries. A previous meta-

unexpectedly low. By ITT analysis, the CR/nCR, ≥VGPR, andanalysis­integrating 4 randomized trials concluded that the≥PR rates after the first ASCT were 31.7%, 43.9%, and 58.5%,

bortezomib-containing induction regimen achieves CR/nCR,

respectively, whereas the IFM 2005-01 trial reported values of

11)≥VGPR, and ≥PR rates of 23%, 47%, and 83%, respectively .

35.0%, 54.3%, and 80.3%, respectively 10), and similar results

One of these trials, the IFM 2005-01 trial which adopted awere obtained in a recent French study 16). Therefore, the RR

BD regimen as induction treatment, achieved CR/nCR, ≥VGPR,

after the first ASCT in the present study was particularly low.

and ≥PR rates of 14.8%, 37.7%, and 78.5%, respectively 10).

We hypothesized that relatively high drop-out rate during and

Because CR/nCR, ≥VGPR, and ≥PR rates in the present study

after the VAD/BD induction chemotherapy, namely 8 and 2 out

were 22.0%, 56.1%, and 85.4%, respectively, the bortezomib-of 41 patients, respectively, adversely affected the post-ASCT

containing regimen may be equally as effective in Japanese

therapeutic outcome.

patients. Furthermore, because the median age was 59 years

In our preceding trial, our study group adopted 3 courses ofand the percentage of patients with ISS stage ≥II disease

VAD as the induction followed by harvesting with either cyclo-

was 63.0%, the characteristics of the patients in the present

phosphamide or etoposide and ASCT. Patients’ backgrounds,

study appeared to be comparable or even disadvantageous

in terms of age, sex, the Durie & Salmon and ISS stage, andin comparison with those in the IFM 2005-01 trial.

serum level of β2 microglobulin, were comparable between

20

International Journal of Myeloma

vol. 5 no. 3 (2015)

BTZ as induction before ASCT for Japanese MM

Table 5.

Comparison of VAD (historical control) and VAD/BD induction
VAD (n = 52)

VAD/BD (n = 41)

No. of Patients (%)

No. of Patients (%)

Response to Induction≥VGPR (ITT)

15/52 (28.8)

23/41 (56.1)

0.011

Response to ASCT≥VGPR (ITT)≥VGPR (Per Protcol)

19/52 (36.5)
19/40 (47.5)

18/41 (43.9)
18/26 (69.2)

0.526
0.127

2   (3.8)
6 (11.5)

8 (19.5)
2   (4.9)

0.020
0.459

1 (1.9)1 (2.4)1.000

Discontinuation during induction
AEs
PD
Withdrawal from agreement/
Physician’s choice

p valuePD, progressive disease; ITT, intention to treat.

these 2 trials (data not shown). Because the VAD regimen

patients proceeded to the first ASCT, which may haveachieved 28.8% of ≥VGPR and 73.1% of ≥PR after induction

adversely affected the therapeutic outcome values. Reflecting

chemotherapy (our unpublished data) (Table 5), the VAD/BD

the higher toxicity of the BD regimen and relatively higher

regimen seems to be superior to VAD in terms of therapeutic

incidence of drop-out throughout the period of chemotherapy

response. However, the superiority of the VAD/BD regimen

prior to ASCT, ITT-based RR after the first ASCT was disappoint-

over VAD for induction didn’t persist after the first ASCT

ing in this study. Indeed, differences in response achieving(≥VGPR: 43.9% versus 36.5%, respectively). Although it may≥VGPR between the VAD and VAD/BD induction regimens

not be rational to directly compare the results of these twowere trivial. Considering that a previous meta-analysis inte-studies, it is highly possible that the favorable response

grating 3 randomized trials comparing bortezomib-based andachieved by the bortezomib-containing induction regimen

non-bortezomib-based induction regimens concluded thatwas suppressed by relatively high incidence of adverse events

the post-ASCT rate of ≥VGPR was significantly higher in theduring and immediately after the induction. To gain insight onbortezomib-based regimen (60% versus 41%, p < 0.001) 11), theprincipal factors contributing to the unfavorable outcomespresent results (rate of ≥VGPR: 43.9%) are clearly inferior toafter completion of the first ASCT in the present study, we

those of the previous meta-analysis. Although the possibility­analyzed the toxicity and safety of the bortezomib-containing

cannot be denied that inclusion of VAD prior to BD in thisinduction regimen and the subsequent PBSCH with cyclo-

study may have had adverse effects, we conclude that the use

phosphamide. Infectious episodes were frequently observedof the BD regimen itself as an induction is toxic to Japanese

during VAD/BD induction, with 2 events during VAD and 7

patients.

events during BD, and 3 patients dropping out due to infection

In conclusion, we believe that a BD-containing induction

during induction. Given that the incidence of grade ≥3 infec-

strategy, despite its durable therapeutic response, possesses

tions observed during BD induction in previously publishedproblems in safety and feasibility of use. As its toxicity maylarge-scale studies conducted in foreign countries was

result in the cessation of treatment, care must be taken in the

12–14% 10,17), Japanese patients may be more vulnerable tomanagement of toxicity when administering BD induction to

infectious complications. High-dose dexamethasone pre-Japanese patients. Although we employed criteria for prolon-

scribed in this study may have resulted in higher incidence ofgation and dose-reduction of chemotherapy in the present

infection during the induction. Similar situation was previously

study referring to preceding foreign studies, these criteria mayreported in a lenalidomide-combined induction chemo­

not be sufficient for Japanese patients. On the other hand, as

18)

therapy . It should also be noted that 4 additional patientsthe relevance of achieving deeper response in the induction

dropped out because of various non-hematologic AEs duringphase before ASCT is now widely accepted, we should also

VAD/BD induction. Consequently, drop-out rates due to AEs

bear in mind not to excessively diminish the therapeuticand disease progression during VAD/BD induction in this study

power of BD induction. From this standpoint, it may be ratio-

were 19.5% and 4.9%, respectively, whereas those during VAD

nal to decrease the dose-intensity of BD for minimizing its

induction were 3.8% and 11.5%, respectively. Because 2 addi-

toxicity, and instead include a third drug to increase the­tional patients dropped out during PBSCH, only 63.4% of thetherapeutic power against myeloma without overlapping­

International Journal of Myeloma

vol. 5 no. 3 (2015)

21

KUDO et al.

­toxicity 19–23). In line with this scenario, we are now con­ducting a phase 2 trial of cyclophosphamide-bortezomibdexamethasone (CyBorD) to prove its efficacy and safety as
induction treatment prior to ASCT in Japanese patients.

Conflict of Interest
The authors declare that they have no conflict of interest.

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