International Journal of Myeloma 4(1): 7–12, 2014
©日本骨髄腫学会

ORIGINAL

Comparison of bortezomib, cyclophosphamide, and dexamethasone(VCD) induction with bortezomib and dexamethasone (BD) induction
for newly diagnosed symptomatic multiple myeloma
Shuichiro TAKASHIMA1, Toshihiro MIYAMOTO1, Tomohiko KAMIMURA2, Goichi YOSHIMOTO1,
Koji KATO1, Yoshikiyo ITO2, Tsuyoshi MUTA1, Takamitsu MATSUSHIMA3, Motoaki SHIRATSUCHI3,
Kazuki TANIMOTO1, Katsuto TAKENAKA1, Hiromi IWASAKI4, Takanori TESHIMA4 and Koichi AKASHI1,4
Bortezomib exerts a synergistic anti-myeloma effect in combination with other novel agents as well as cytotoxic
drugs. In this study, we examined the efficacy and safety of the combination regimen bortezomib, cyclophosphamide,
and dexamethasone (VCD) in comparison with the combination regimen bortezomib and dexamethasone (BD) in
Japanese patients with multiple myeloma (MM). Twenty-two newly diagnosed MM patients treated with threecycles of either BD (n = 10) or VCD (n = 12) were enrolled in this study. We found no significant difference in cumulative
dose (p = 0.29) for bortezomib between the two groups, indicating that the addition of cyclophosphamide did not
require reduction of bortezomib dosage. There was no significant difference in overall response rate (90% vs 83%,
respectively; p = 0.57) as well as very good partial response or better response rate (40% vs 17%, respectively; p =0.23) after treatment between the BD and VCD groups. Grade 3–4 neutropenia as well as peripheral neuropathy wascomparable between the two groups (p = 0.29 and 0.19, respectively). Thus, the addition of cyclophosphamide did
not exacerbate adverse events. Modification of the regimen may be necessary for further validation of the efficacy
of VCD.
Key words:

multiple myeloma, bortezomib, cyclophophamide, induction therapy

Introduction

transplantation (ASCT) was clearly demonstrated in the IFM
2005-01 Phase III trial 2). In this study, bortezomib + dexameth-

The treatment of multiple myeloma (MM) has been dramati-

asone (BD) significantly improved post-induction and post-

cally changed by the introduction of novel agents includingtransplantation response rates compared with vincristine +thalidomide, bortezomib, and lenalidomide 1). Among thesedoxorubicin + dexamethasone (VAD), which was previously

new drugs, bortezomib can rapidly achieve a profound effect,

the standard induction therapy. Other studies also demon-and its value in induction therapy before autologous stem cellstrated that BD yields high response rates post-induction andReceived: October 9, 2013, accepted: January 7, 2014
1
Department of Medicine and Biosystemic Science, Kyushu
University Graduate School of Medical Sciences2
Department of Hematology, Harasanshin Hospital3
Department of Medicine and Bioregulatory Science, Kyushu
University Graduate School of Medical Sciences
4
Center for Cellular and Molecular Medicine, Kyushu University
Hospital
Corresponding author: Toshihiro MIYAMOTO, MD, PhD
Department of Medicine and Biosystemic Science, Kyushu
University Graduate School of Medical Sciences, 3-1-1 Maidashi,
Higashi-ku, Fukuoka 812-8582, Japan
TEL: 81-92-642-5230, FAX: 81-92-642-5247
E-mail: toshmiya@intmed1.med.kyushu-u.ac.jp

post-ASCT in newly diagnosed MM patients 3,4). These results
clearly revealed that the BD regimen would be one of theefficacious induction therapies prior to ASCT in the treatmentof newly diagnosed MM.
In addition, experimental data showed that the combinationof bortezomib and cytotoxic agents such as melphalan ordoxorubicin delivers synergic anti-myeloma effects 5,6). In fact,
the addition of a third agent to BD has been associated withhigher response rates in the treatment of MM 7–9). The major
combinations of bortezomib-containing regimens include
bortezomib + dexamethasone + intravenous cyclophosphamide(VCD or CyBorD), bortezomib + adriamycin + dexamethasone(PAD), bortezomib + thalidomide + dexamethasone (VTD), andbortezomib + dexamethasone + lenalidomide (VRD), although

International Journal of Myeloma

vol. 4 no. 1 (2014)7

the optimal combination of induction therapy before ASCT

tion of therapy-related toxicities. Prophylactic antibiotics forremains to be determined 7–10). Because of the high cost of

Pneumocystis jirovecii and valacyclovir for herpes zoster weretreatment regimens such as VTD and VRD, VCD represents aalso administered.

promising candidate for initial therapy, with a high response
rate equivalent to that of VRD or VTD, and several ongoing

Statistical analysis

clinical trials are now evaluating the efficacy and safety of thisThe aim of this study was to compare response rates andregimen in patients with both newly diagnosed and relapsed/

toxicity profiles between the BD and VCD regimens as induc-refractory MM 8,11–15). However, to our knowledge, only few

tion therapy for newly diagnosed MM. All patients werereports have compared the efficacy and safety of the BD andassessed for responses using the International Myeloma Work-VCD regimens 16).

ing Group criteria after three cycles of treatment 17), andIn Japan, the combination therapy of bortezomib with othertherapy-related toxicity was graded according to the National

cytotoxic agents was sanctioned in September 2011, whereas

Cancer Institute Common Toxicity Criteria (NCI CTC) version

the application for lenalidomide and thalidomide as the first

4.0. Chi-square testing was used for univariate comparison toline of treatment for newly diagnosed MM has not been

examine categorical variables, and the Mann-Whitney test

accepted at the time of submission of this article. Thus, the use

was used to compare numerical variables. p-value < 0.05 wereof bortezomib-containing regimens such as VCD has recently

considered statistically significant.

been introduced for the treatment of newly diagnosed MM,

Results

and the efficacy and safety of these regimens have not yet
been established for Japanese patients. In this study, we evaluated the efficacy and safety of VCD induction in the treatment
of Japanese patients with newly diagnosed MM, and compared our findings with those for the BD regimen.

Patients
Patient characteristics are summarized in Table 1. Baseline
parameters (age, sex, myeloma subtype, and International
Staging System stage) were similar between the two groups.

Patients and Methods

G-banding cytogenetic analysis of marrow aspirates revealed acomplex karyotype in one patient of the BD group and two

Patients

patients of the VCD group. t(4;14) and deletion 17p13, which

This was a retrospective analysis of 12 patients withare regarded as high-risk cytogenetic abnormalities 18), were

symptomatic MM who were treated with three cycles of VCD

detected by fluorescence in situ hybridization in each one

regimen at Kyushu University Hospital between September

Table 1.

2011 and April 2013. 10 patients receiving three cycles of BD

Patients characteristics
BD (n=10)

regimen between April 2010 and August 2011 were selected

VCD (n=12)

P-value59.5 (39–70) 53.5 (34–70)

0.28

for the historical control group. All patients provided informed

Median age (years), range

consent, and this study was approved by the Institutional

Male sex, n (%)

6 (60)

6 (50)

Myeloma type, n (%)
IgG
IgA
IgD
Bence Jones Protein
non-secretary

5 (50)
1 (10)
1 (10)
2 (20)
1 (10)

8 (67)
3 (25)01 (8)0karyotype, n (%)
normalcomplexN.E.

7 (70)
1 (10)
2 (20)

10 (83)2 (17)
0

FISH, n (%)
t(4;14)–17p130
1 (10)1 (8)0Review Board of Kyushu University Hospital.
Treatment regimens
In the BD group, after short-term administration of highdose dexamethasone, bortezomib was administered at a doseof 1.3 mg/m2 on days 1, 4, 8, and 11, with dexamethasone(20 mg) on days 1–2, 4–5, 8–9 and 11–12. In the VCD group,
bortezomib dosage was identical to that in the BD group,with the addition of cyclophophamide (500 mg/m2 on days 1
and 8), and dexamethasone (40 mg) on days 1, 4, 8, and 11,
i.e. “twice weekly VCD”. In another “once weekly VCD” regimen, bortezomib was administered at a dose of 1.3 mg/m2,
plus cyclophosphamide (300 mg/m2), and dexamethasone(40 mg) on days 1, 8, 15, and 22. Cyclophophamide was all
administered intravenously.
Patients received granulocyte colony-stimulating factor,
bisphosphonates, and transfusions as necessary for ameliora8

International Journal of Myeloma

vol. 4 no. 1 (2014)

0.82

N.E.

N.E.

International Staging System stage, n (%)
I
3 (30)
II
3 (30)
III
4 (40)
Abbreviations; N.E.: not examined

0.48

0.37
5 (42)
4 (33)
3 (25)

Table 2.

group (p = 0.57). One patient remained stable disease (SD) in

Treatment exposure and response
BD (n=10)

VCD (n=12)

P-valueMedian cumulative dose of
bortezomib (mg/m2), range

15.6(10.4–15.6)

15.6(14–15.6)

0.29

Mean dose of bortezomib
per cycle (mg/m2), range

4.9(3.5–5.2)

5.2(4.7–5.2)

0.29

Best response across all cycles, n (%)
Complete response
1 (10)VGPR or better
4 (40)ORR (PR or better)
9 (90)
Stable disease
1 (10)
Progressive disease0

1 (8)2 (17)
10 (83)2 (17)
0

0.71
0.23
0.57
0.57
N.E.

the BD group, while two patients remained SD in the VCD
group (Table 2).
We also evaluated reduction rates per cycle for serum
M-protein levels, as shown in Figure 1, to compare the parameters between the two regimens. Contrary to our expectations,
there was no significant difference in reduction rates ofAbbreviations; VGPR: very good partial response, ORR: overall response
rate, PR: partial response, N.E.: not

M-protein levels between the groups.
Adverse events during VCD treatment
Adverse events observed during BD or VCD treatment are
shown in Table 3. Although grade 1–4 neutropenia was morecommon in the VCD group than in the BD group (83% vs 30%;
p = 0.02), the incidence of severe grade 3–4 neutropenia wassimilar between the groups (17% vs 0%; p = 0.29). No signifi-

100

cant difference was observed in regard to thrombocytopenia%M-protein

80

P=0.30P=0.56and anemia between the groups (p = 0.42 and 0.45, respec-

P=0.39

60

BD
VCD

40
20
0

tively). No case in both groups required bortezomib dose
reduction on account of severe cytopenia.
Peripheral neuropathy was the most common non-hematological toxicity in both groups, and the incidence and severityof peripheral neuropathy were similar between the groups (p

0

1

2

3

Cycles of induction
Figure 1. Reduction rates of serum M protein levels in the first threecycles. Serum levels of M protein were seriously measured after
each cycle of BD or VCD regimen, and compared to that at­diagnosis. Data are shown as means ± SD.

= 0.22). Other adverse events included infection, liver dysfunction, and skin eruption, as shown in Table 3. One case in
the BD group developed grade 3 bacterial pneumonia, which
responded well to antibiotics, and three cycles of BD treatment
were completed as scheduled. Elevated serum aspartate
amino transferase (AST) and alanine amino transferase (ALT)levels were detected in two (20%) and five (42%) patients ofpatient. Six out of 10 patients (60%) and ten out of 12 patients

the BD and VCD group, respectively (p = 0.27). Levels of AST(83%) treated by BD and VCD regimen, respectively, underwent
subsequent ASCT. Three patients received “twice weekly VCD”

Table 3.

Adverse events

alone, while nine patients received “twice weekly VCD” followedBD(n=10)

VCD(n=12)

P-value

3 (30)0

10 (83)2 (17)

0.02
0.29

Thrombocytopenia (grade 1–4)
Thrombocytopenia (grade 3–4)

8 (80)
3 (30)

8 (67)
2 (17)

0.42
0.41

Anemia (grade 1–4)
Anemia (grade 3–4)

9 (90)
1 (10)

12 (100)
0

0.45
0.45

9 (90)
2 (20)

8 (67)
0

0.22
0.19

Infection (grade 1–4)
Infection (grade 3–4)

1 (10)
1 (10)

0
0

0.45
0.45

Liver dysfunction (grade 1–4)
Liver dysfunction (grade 3–4)

2 (20)
0

5 (42)
2 (17)

0.27
0.29

Skin eruption

3 (30)

1 (8)

0.23

by “once weekly VCD”. Three out of nine patients changed theschedule from “twice weekly VCD” to “once weekly VCD”
because of cytopenia, while the others changed the scheduledue to the convenience in the outpatient department.
Treatment response
The median cumulative dose of bortezomib in three cycles2

was 15.6 mg/m (range, 10.4–15.6) in the BD group and 15.6
mg/m2 (range, 14.0–15.6) in the VCD group (p = 0.29), respectively. Complete response (CR) was achieved in one patient(10%) in the BD group and in one patient (8%) in the VCD
group (p = 0.71). Of note, the patient who achieved CR in VCD
group was one of the three patients received “twice weekly
VCD” alone. Very good partial response (VGPR) or better
response rate was 40% (4/10) in the BD group and 17% (2/12)
in the VCD group (p = 0.23). Overall response rate (≥PR, ORR)
was 90% (9/10) in the BD group and 83% (10/12) in the VCD

Hematological AEs, n (%)
Neutropenia (grade 1–4)
Neutropenia (grade 3–4)

Nonhematological AEs
Peripheral neuropathy (grade 1–4)
Peripheral neuropathy (grade 3–4)

Abbreviations; AE: adverse events

International Journal of Myeloma

vol. 4 no. 1 (2014)9and ALT were quickly normalized with supportive care in mostthe two groups (Table 2), and the superiority of VCD over BD

cases except two cases (one from each group), which required

as shown in a previous study 16) was not demonstrated here.

reduction of bortezomib dose. Skin eruption was documented

The relative small number of cases in our study might make itin three patients in the BD group, and one in the VCD groupdifficult to detect subtle differences in response rates between(p = 0.23).

the two regimens, because the response rate in the BD group

Concerning the difference in toxicity profiles between(ORR, 90%) was relatively high, as reported previously (47.0%–“twice weekly VCD” and “once weekly VCD”, neutropenia and87.5%) 2–4,16). To examine the effectiveness of induction therapy

thrombocytopenia were significantly more common in the

more precisely, we compared the reduction rates for serum

twice weekly schedule than in the once weekly schedule,

M-protein levels in the first three cycles, but these were foundalthough anemia and non-hematological adverse events wereagain to be comparable between the two groups (Figure 1).

similar between the two schedules (data not shown).

In the EVOLUTION study, the increase of additional cyclo­

The VCD regimen did not significantly increase the inci-

phosphamide to BD enhanced treatment efficacy 11), sug­

dence and severity of hematological and non-hematologicalgesting that the amount of additional cyclophsophamide inadverse events. In a total, although bortezomib dosage was

our study might not be enough to augment the synergistic

reduced in two patients as mentioned above, treatment wasanti-myeloma effect of bortezomib. Alternatively, “once weekly

not discontinued despite any adverse events.

VCD” regimen might have impaired the treatment efficacy of
VCD in our study, because once weekly administration of

Discussion­bortezomib might be inferior to twice weekly administrationin terms of dose intensity 21). Thus, intensification of VCD by
19)

Bortezomib acts solely as a novel anti-myeloma agent ,increase of additional cyclophosphamide to BD or intensifica-

however, experimental studies have shown that bortezomib

tion of bortezomib administration schedule (i.e. abolition offurther augments the effects of cytotoxic agents including“once weekly VCD”) might reveal the superiority of VCD overmelphalan and doxorubicin

5,6). On the basis of these results,

the combination therapy of bortezomib and cytotoxic agents,

BD. “Modified VCD” employed in the EVOLUTION study might
represent one of the efficacious protocols of VCD regimen.

as well as other novel agents, has been verified by several

Considering that achievement of VGPR or better response

clinical trials 7–11,15,20). In these trials, the VCD regimen was

before ASCT is a strong prognostic factor for longer PFS 22),

shown to provide marked response rates equivalent to thosepost induction VGPR or better response rates in our study (17–of VRD or VTD (post-induction ORR, 85%–100%) 7,9,11,20), and40%) were not satisfactory despite relative high ORR in boththerefore, in terms of cost effectiveness, the VCD regimengroups. This might be partially due to the relative small

would appear to have an advantage over VRD and VTD.

number of treatment cycles (three cycles in both groups).

Reeder et al. reported the efficacy of the CyBorD regimen as

The maximum effect of VCD may be observed after four oran induction therapy for 33 newly diagnosed MM patients, andmore cycles of treatment, because several clinical trials withdemonstrated an ORR of 88% with VGPR and CR rates of

VMP therapy suggested that at least 16 bortezomib admin­

61% and 39%, respectively after four cycles of treatment 15).

istrations were required to achieve CR 23–25). Subcutaneous

In the EVOLUTION study, after a median six cycles, ORR was

administration of bortezomib 26–28), which was sanctioned inreportedly 75% and 100% for the original VCD (bortezomib at

December 2012 in Japan, might help to increase cumulative2

a dose of 1.3 mg/m on days 1, 4, 8, and 11 + dexamethasone

dose of bortezomib without exacerbating peripheral neuropathy.

at a dose of 40 mg on days 1, 4, 8 and 11 + cyclophophamide

Our study showed that the incidence of adverse events in

2

at a dose of 500 mg/m on days 1 and 8) and modified VCD

the VCD regimen was comparable to those of the BD regimen.

(original VCD + cyclophosphamide at 500 mg/m2 on day 15)

Neutropenia was more common in the VCD group than in thearms, respectively, with VGPR or better response rates of 41%

BD group, whereas the frequency of grade 3–4 severe neutro-

and 53%, respectively 11). Considering that the usage ofpenia was similar between groups. The incidence and severity

lenalidomide and thalidomide has not yet been sanctioned inof thrombocytopenia and anemia was also comparable

the treatment of newly diagnosed MM in Japan, it is crucial to

between the two groups. These results suggest that cyclo-

evaluate the efficacy and safety of the VCD regimen as anphosphamide in combination with bortezomib and dexa-

induction therapy for Japanese MM patients.

methasone does not exacerbate myelosuppression. Nine out

In this study, we retrospectively examined the efficacy andof ten patients in the BD group and eight out of 12 patientssafety of the VCD regimen in the treatment of newly diag-

in VCD group developed peripheral neuropathy, which was

nosed MM patients, and compared this regimen with the BD

the most common non-hematological adverse event in bothregimen. Post-induction CR and ORR were similar between

groups. Peripheral neuropathy was tolerable and manage-

10

International Journal of Myeloma

vol. 4 no. 1 (2014)

able with supportive therapy in most cases, and reduction ofal. Bortezomib with thalidomide plus dexamethasone comparedbortezomib dose was required in only one case. It should bewith thalidomide plus dexamethasone as induction therapy

emphasized that the addition of cyclophosphamide to the BD
regimen did not exacerbate the incidence and severity of
peripheral neuropathy as well as other non-hematologicaladverse events.

before, and consolidation therapy after, double autologous
stem-cell transplantation in newly diagnosed multiple myeloma:
a randomised phase 3 study. Lancet. 2010; 376: 2075-85.
8) Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Hentz J, et al.
Cyclophosphamide, bortezomib and dexamethasone induction

Despite small number of cases, the superiority of VCD overBD was not obvious in this study, and three cycles of VCD in
the current form may be insufficient as an induction therapy
prior to ASCT. On the other hand, when one examines the data
for adverse events, induction therapy with VCD may be as safe

for newly diagnosed multiple myeloma: high response rates in aphase II clinical trial. Leukemia. 2009; 23: 1337-41.
9) Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S,
Raje NS, et al. Lenalidomide, bortezomib, and dexamethasone
combination therapy in patients with newly diagnosed multiple
myeloma. Blood. 2010; 116: 679-86.

as BD in Japanese patients. The efficacy of this regimen needs

10) Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch

to be evaluated in an intensified fashion in combination with

U, Salwender H, et al. Bortezomib Induction and Maintenance

ASCT in the future.

Treatment in Patients With Newly Diagnosed Multiple Myeloma:
Results of the Randomized Phase III HOVON-65/ GMMG-HD4 Trial.

Acknowledgement
We appreciate the medical and nursing staff working on
Kyushu University Hospital. This work was supported by JSPS
KAKENHI (24790977 to S.T.).

J Clin Oncol. 2012; 30: 2946-55.
11) Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ, et al.
Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, andlenalidomide in previously untreated multiple myeloma. Blood.
2012; 119: 4375-82.
12) Khan ML, Reeder CB, Kumar SK, Lacy MQ, Reece DE, Dispenzieri

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

A, et al. A comparison of lenalidomide/dexamethasone versus
cyclophosphamide/lenalidomide/dexamethasone versus cyclophosphamide/bortezomib/dexamethasone in newly diagnosed
multiple myeloma. Br J Haematol. 2012; 156: 326-33.
13) Fu W, Delasalle K, Wang J, Song S, Hou J, Alexanian R, et al.

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