‘‘Short Course’’ Bortezomib plus Melphalan and

Prednisone as Induction Prior to Transplant or as

Frontline Therapy for Nontransplant Candidates in
Patients with Previously Untreated Multiple Myeloma
Cristina Gasparetto,1 Jon P. Gockerman,2 Louis F. Diehl,2 Carlos M. de Castro,2
Joseph O. Moore,2 Gwynn D. Long,1 Mitchell E. Horwitz,1 George Keogh,3 John P. Chute,1
Keith M. Sullivan,1 Rachel Neuwirth,4 Patricia H. Davis,1 Linda M. Sutton,5
Russell D. Anderson,5 Nelson J. Chao,1 David Rizzieri1

The purpose of this study was to evaluate the efficacy and safety of short-course bortezomib, melphalan,
prednisone (VMP) in previously untreated multiple myeloma as frontline therapy for transplant-ineligible pa-
tients and induction prior to autologous stem cell transplantation (ASCT). Patients received up to 6 28-day
cycles of bortezomib 1.3 mg/m2, days 1, 4, 8, and 11, plus melphalan 6 mg/m2 and prednisone 60 mg/m2, days
1-7. After 2-6 cycles, eligible and consenting patients could proceed to ASCT. Responses were assessed by
International Uniform Response Criteria. The primary endpoint was complete response (CR) rate with VMP.
Forty-five patients were enrolled. Among 44 evaluable patients, response rate was 95%, including 18% $CR
(9% stringent CR), 27% very good partial responses (VGPR), and 50% partial responses (PR). Twenty patients
proceeded to ASCT. Stem cell collection was successful in all; median yield was 5.6106 CD341 cells/kg.
Posttransplant response rates were 30% $CR (10% stringent CR), 65% VGPR, and 5% PR. After median fol-
low-up of 14.0/14.6 months, median time to progression and progression-free survival were both 19.8/27.9
months in non-ASCT/ASCT patients. Seven patients have died; 1-year survival rates were 82%/95% in non-
ASCT/ASCT patients. The most common grade 3/4 toxicities were thrombocytopenia (20%), neutropenia
(28%), and infection (9%). Peripheral neuropathy grade 2-4 was the most common nonhematopoietic side
effect occurring 17 patients (38%), although it was typically reversible, and only 5 patients (11%) discontinued
therapy as a result of it. Short-course VMP is highly effective and generally well tolerated, both as initial treat-
ment in non-ASCT patients and induction prior to ASCT. VMP did not negatively affect stem cell collection.
Longer follow-up and prospective phase III trials are required to validate these initial observations.
Biol Blood Marrow Transplant 16: 70-77 (2010) Ó 2010 American Society for Blood and Marrow Transplantation

KEY WORDS: Multiple myeloma, Autologous transplantation, Induction therapy

INTRODUCTION
Multiple myeloma (MM) is a B cell lymphoproli-
ferative disorder that accounts for approximately
10% of all hematologic malignancies [1]. High-dose
melphalan (Mel) therapy plus autologous stem cell
transplant (ASCT) remains 1 of the preferred ap-
proaches in previously untreated MM patients aged
#65 years, having been shown to result in superior

From the 1Cellular Therapy, Duke University Medical Center, Dur-
ham, North Carolina; 2Oncology–Hematology, Duke Univer-
sity Medical Center, Durham, North Carolina; 3Charleston
Hematology Oncology Associates, PA Charleston, South Caro-
lina; 4Millennium Pharmaceuticals, Inc., Cambridge, Massa-
chusetts; and 5Duke Oncology Network, Duke University
Medical Center, Durham, North Carolina.
Previous presentations and publications containing material appear-
ing in this manuscript: Gasparetto C, Gockerman JP, Diehl LF,
et al. Bortezomib plus melphalan and prednisone as induction
prior to transplant or as frontline therapy for non-transplant
candidates in patients with previously untreated multiple mye-
loma. Blood. 2008;112:abstract 3325. Poster presented at 2008
Annual Meeting of the American Society for Hematology, San
Francisco, CA, December 6-9. Gasparetto C, Keogh GP, Gock-
erman JP, et al. A prospective study of bortezomib in combina-
tion with melphalan and prednisone for patients with previously
untreated multiple myeloma. Blood. 2005;106:379b (abstract
5181).
Financial disclosure: See Acknowledgments on page 76.
Correspondence and reprint requests: Cristina Gasparetto, MD, De-
partment of Cellular Therapy, Duke University Medical Cen-
ter, Durham, NC, 27710 (e-mail: gaspa001@mc.duke.edu).
Ó 2010 American Society for Blood and Marrow Transplantation
1083-8791/10/161-0008$36.00/0
doi:10.1016/j.bbmt.2009.08.017

70
Biol Blood Marrow Transplant 16:70-77, 2010 VMP Therapy in Frontline MM Patients Eligible/Ineligible for ASCT
response rates and improved outcomes, including
prolonged overall survival (OS), compared with con-
ventional chemotherapy alone [2-4]. In preparation
for ASCT, patients typically receive induction therapy
to reduce their tumor burden. Achievement of a com-
plete (CR) or very good partial response (VGPR) to
induction therapy or following transplant has been
associated with improved outcomes, including pro-
longed time to progression (TTP), progression-free
survival (PFS), and OS [5]. Higher rates of CR/
VGPR following induction therapy may result in
higher rates posttransplant, leading to longer OS [6-
8]; therefore, optimizing response to induction ther-
apy remains an important goal.
With this aim, a wide variety of induction regimens
are being explored. Bortezomib-based regimens are
demonstrating substantial activity, with very high rates
of CR/VGPR, in patients with previously untreated
MM [9], including induction therapy prior to ASCT
[6-8]. These clinical findings reflect preclinical investi-
gations in which bortezomib showed synergistic or
additive activity in combination with agents commonly
used for the treatment of MM, including Mel [10,11],
doxorubicin [10,11], dexamethasone [12], and the im-
munomodulatory agents [13].
Notably, Mitsiades et al. [10,11] demonstrated that
bortezomib greatly increased the sensitivity of MM cell
lines and patients’ cells to Mel in vitro, including for-
merly Mel-resistant cell lines. In phase 1/2 clinical tri-
als, bortezomib plus melphalan resulted in promising
activity in relapsed or refractory MM patients [14],
and subsequently in a Spanish Myeloma Group trial
bortezomib plus melphalan–prednisone (VMP) pro-
duced an 89% response rate, including 32% CR, in
previously untreated MM patients aged $65 years
not proceeding to ASCT [15,16].
However, lengthy MP-based therapy is not typi-
cally used for transplant-eligible MM patients because
prolonged treatment with Mel can adversely affect pe-
ripheral blood stem cell collection [17]. In contrast,
short-term Mel therapy may not significantly impair
stem cell harvesting [18]. Based on the importance of
attaining a CR/VGPR prior to ASCT, and the effec-
tiveness of bortezomib in combination with Mel, this
phase II study was conducted to evaluate whether
a short course of a modified VMP regimen would be
effective and tolerable both as frontline therapy in
non-ASCT patients and as induction therapy prior to
transplant.
PATIENTS AND METHODS
Patient Selection
Patients aged $18 years with previously untreated
(except localized radiotherapy), histologically con-
firmed MM were eligible. Other inclusion criteria
71
included Eastern Cooperative Oncology Group
(ECOG) performance status #3, life expectancy .3
months, and normal organ and marrow function
(leukocytes $3109/L, absolute neutrophil count
[ANC] $1.5109/L, platelets $100109/L, serum
creatinine #3.5 mg/dL, aspartate aminotransferase
[AST]/alanine aminotransferase [ALT] #2.5  upper
limit of normal, total bilirubin within normal institu-
tional limits). Patients with severe pancytopenia be-
cause of MM bone marrow (BM) involvement and
renal insufficiency (serum creatinine .2 mg/dL) be-
cause of MM were eligible. Patients were excluded if
they were HIV-positive, had history of hepatitis C vi-
rus (HCV) infection, or had other uncontrolled inter-
current illness limiting compliance with study
requirements. Ineligibility for ASCT was not an exclu-
sion criterion. All patients provided written informed
consent. The study was approved by the Cancer Proto-
col Committee at Duke University Medical Center
(DUMC) as well as by the institutional review board
at DUMC and the review boards at all participating
centers, and was conducted in accordance with Inter-
national Conference on Harmonization guidelines
on Good Clinical Practice and the principles of the
Declaration of Helsinki.
Study Design
This prospective, openrf-label phase II clinical
trial was conducted at DUMC, Durham, NC, and 2
centers in the Duke Oncology Network (Johnston
Memorial Hospital, Smithfield, NC, and Person Me-
morial Hospital, Roxboro, NC). Patients were en-
rolled from August 5, 2004, to August 31, 2007.
The primary end points were CR/VGPR rate with
VMP and safety, durability of response and ability
to collect stem cell postinduction. All patients signed
informed consent prior initiation of therapy and the
protocol was approved by the local IRB (institutional
review board).
Patients received up to 6 28-day cycles of i.v. borte-
zomib 1.3 mg/m2, days 1, 4, 8, and 11, plus oral Mel 6
mg/m2 and prednisone 60 mg/m2, days 1-7. On days of
concurrent administration, Mel was administered at
least 1 hour prior to bortezomib. Permitted supportive
therapy included hematopoietic growth factors after
cycle 1, and standard antiemetic agents; bisphospho-
nates were recommended as standard therapy, and acy-
clovir was recommended for herpes zoster prophylaxis.
Patients discontinued treatment because of disease
progression, unacceptable adverse events (AEs), or in-
tercurrent illness preventing further treatment admin-
istration, or based on patient/investigator decision.
Patients could continue to receive treatment beyond
6 cycles at the discretion of the investigator. Dose
reductions were permitted after cycle 1; bortezomib
dose reductions were required for greater than grade
72 C. Gasparetto et al. Biol Blood Marrow Transplant 16:70-77, 2010

2 bortezomib-related peripheral neuropathy using es- Statistical Analysis

tablished dose modifications [19]. Mel and prednisone
were withheld for any grade $3 nonhematologic or
grade 4 hematologic toxicity, and reinitiated without
dose reduction upon resolution.
All patients were to receive a minimum of 2 cycles of
therapy up to a maximum of 6 cycles. Patients who
achieved a CR/VGPR proceeded to ASCT at the point
this was first documented (between cycles 2 and 6). All
patients were mobilized with growth factors, although
2 had the addition of cyclophosphamide. The condition-
ing regimen was Mel 200 mg/m2 (140 mg/m2 if aged
.65 years).
A sample size of 45 was required to detect a CR rate
of 20% with VMP compared with 5% in historical
controls receiving MP, assuming a 5 0.073 (1 sided)
and 96% power. PFS and OS were defined as time
from first dose until progression or death, or until
last follow-up or death, respectively. TTP, PFS, and
OS distributions were estimated using the Kaplan-
Meier method. Descriptive statistics are presented sep-
arately for non-ASCT and ASCT patients as a post hoc
subgroup analysis.

Assessments
Hematology and serum chemistry were assessed at
baseline, in weeks 1 and 2 of each cycle, and at the end
of treatment. Performance status was determined at
baseline, the start of each cycle, and the end of treat-
ment. Blood and urine samples for M-protein mea-
surement were collected, and bone marrow aspirate
and biopsy performed, at baseline, every 2 cycles dur-
ing induction, and upon completion of treatment. Re-
sponse was assessed every 2 cycles and post-ASCT.
Although this was a prospective study, to grade efficacy
we applied the more stringent recently published
International Uniform Response Criteria [20].
Patients who proceeded to ASCT were followed every
3 months for the first year and every 3 to 6 months
thereafter. AEs were monitored throughout induction
and graded according to the National Cancer Institute
(NCI) Common Terminology Criteria for Adverse
Events (CTCAE) version 3.0.
RESULTS
Patient Characteristics
Forty-five patients were enrolled, of whom 20
proceeded to ASCT. Patients’ baseline demographics
and disease characteristics are listed in Table 1, overall,
and by ASCT status. Overall, 60% of patients were
male, median age was 63 years, 37% had International
Staging System [21] (ISS) Stage III disease, 22% had
ECOG performance status .1, and 70% had $40%
plasma cells in their BM; the MM subtype was IgG
in 67%, IgA in 16%, and kappa or lambda light chain
in 9% each. Cytogenetic and fluorescein in situ hy-
bridization (FISH) analyses were performed in 37
patients (Table 1). Among non-ASCT versus ASCT
patients, median age was higher (66 versus 54 years),
and proportions of patients with albumin \3 g/dL,
b2-microglobulin $3.5 mg/L, ISS Stage III disease,
ECOG performance status .1, and BM plasma cell
infiltration $40% appeared somewhat higher; in

Table 1. Baseline Patient Demographics and Disease Characteristics Overall and According to Transplant Status
Total N545 Non-ASCT Patients N525 ASCT Patients N520

Median age, years (range) 63 (33-75) 66 (43-75) 54 (33-74)

Male, n (%) 27 (60) 15 (60) 12 (60)
Albumin <3 g/dL, n (%) 5 (11) 4 (16) 1 (5)
b2-microglobulin $3.5 mg/L, n/N (%) 21/38 (55) 12/19 (63) 9/19 (47)
ISS stage, n (%) n538 n518 n520
I/II 24 (63) 10 (56) 14 (70)
III 14 (37) 8 (44) 6 (30)
Creatinine >2.5 mg/dL, n (%) 2 (4) 1 (4) 1 (5)
ECOG PS >1 10 (22) 9 (36) 1 (5)
Bone marrow plasma cell 30/43 (70) 19/24 (79) 11/19 (58)
infiltration $40%, n/N (%)
MM isotype, n (%)
IgG 30 (67) 18 (72) 12 (60)
IgA 7 (16) 2 (8) 5 (25)
Light chain
Kappa 4 (9) 3 (12) 1 (5)
Lambda 4 (9) 2 (8) 2 (10)
Cytogenetic abnormalities, n (%) n537 n521 n516
del(13) 10 (27) 7 (33) 3 (19)
del(17 p) 5 (13) 3 (14) 2 (13)
t(11;14) 7 (19) 5 (24) 2 (13)
Hyperdiploidy 2 (5) 1 (5) 1 (6)
Hypodiploidy 1 (3) 1 (5) —

ASCT indicates autologous stem cell transplantation; ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System.
Biol Blood Marrow Transplant 16:70-77, 2010 VMP Therapy in Frontline MM Patients Eligible/Ineligible for ASCT 73

addition, rates of chromosome 13 deletion and t(11;14)
appeared slightly higher in non-ASCT patients.
Treatment Exposure
Patients received a median of 4 cycles of VMP
(range: 1-6 in non-ASCT patients; range: 2-6 in
ASCT patients). Ninteen patients discontinued VMP
prior to completing 6 cycles for reasons other than
proceeding to transplant; these included AEs in 11 pa-
tients, disease progression in 5 (no response in 2, early
response followed by relapse in 3), and withdrawal of
consent in 3. Only 1 patient failed to complete the first
cycle, because of development of grade 3 pneumonia
and subsequent early withdrawal of informed consent
prior to receiving thalidomide-dexamethasone. Con-
sequently, only 44 patients were evaluable for
response, all of whom received 2 cycles of therapy.
The 24 evaluable non-ASCT patients did not receive
any additional therapy until relapse or progression;
of these, 22 elected not to proceed to transplant or
were removed from the study by the referring physi-
cian, and 2 developed toxicity during VMP (chest
pain, and myocardial infarction, respectively, both
with a history of coronary artery disease, resulting in
withdrawal of consent), which rendered them ineligi-
ble for ASCT according to institutional guidelines.
Response to VMP
Best responses to VMP overall and by treatment
cycle in which they were achieved are shown in Table
2. Responses were seen in 42 of 44 (95%) evaluable pa-
tients, and included 18% CR or better (9% stringent
CR [sCR], 9% CR), 27% VGPR, and 50% PR. The
2 patients who failed to respond to therapy completed
only the first cycle and 2 cycles of therapy, respectively.
Responses to VMP were rapid; best response was
achieved after cycle 2 in 10 patients, cycle 4 in 25 pa-
tients, and cycle 6 in 7 patients.
Best responses to VMP by ASCT status are shown
in Table 3. Among 24 evaluable patients who did not
proceed to transplant, overall response rate was 92%,
which included 25% $CR (8% sCR, 17% CR), 17%
VGPR (42% $VGPR), and 50% PR. All 20 ASCT
patients achieved a response prior to transplant,
including 2 (10%) sCR, 8 (40%) VGPR, and 10
(50%) PR.
Stem Cell Harvest and ASCT
Following VMP induction, 1 patient received an
additional cycle of therapy with bortezomib plus lipo-
somal doxorubicin prior to ASCT, and 1 patient devel-
oped grade 3 peripheral neuropathy after 4 cycles of
VMP and received 2 cycles of lenalidomide plus low-
dose dexamethasone prior to transplant. All 20
ASCT patients met stem cell collection requirements
(.2106 CD341 cells/kg), and 14 (70%) achieved
yields of (.5106 CD341 cells/kg). Median yield
was 5.6106 CD341 cells/kg (range: 2.3-12.2106
cells/kg), collected in a median of 2 aphaeresis (range:
1-4). Of the 20 ASCT patients, 18 received Mel 200
mg/m2 as conditioning and 2 patients aged .65
years received Mel 140 mg/m2. Median day of neutro-
phils recovery (.500109/L) following stem cell
reinfusion was day 11, with a median of 5 days of severe
neutropenia. Median day of platelet recovery
(.20,000109/L) following stem cell reinfusion was
day 13.
Posttransplant response rates were 30% $CR
(10% sCR, 20% CR), 65% VGPR, and 5% PR. This
represented an improvement in equal to or more
than VGPR rate from 50% pretransplant to 95%
post-ASCT. Response improved from completion of
VMP to post-ASCT in 11 patients; 7 improved from
PR to VGPR, 2 from PR to CR, and 2 from VGPR
to CR.
Outcomes
After median follow-up of 14.0 months (range: 7.4-
47.7) in non-ASCT patients and 14.6 months (range:
8.2-42.9) in ASCT patients, median TTP and PFS

Table 2. Best Response to VMP, Overall and by Treatment Table 3. Best Response to VMP by Transplant Status, and
Cycle Best Response post-ASCT in Patients Proceeding to Trans-
plant
Cycle by Which
Best Response Achieved ASCT Patients, N520

Best Response Non-ASCT

Response rate, n (%)* to VMP N 5 44 2 4 6 Response rate, n (%) patients, N524 Pretransplant Posttransplant

$CR 8 (18) 1 4 3 $CR 6 (25) 2 (10) 6 (30)

sCR 4 (9) 1 3 — sCR 2 (8) 2 (10) 2 (10)
CR 4 (9) — 1 3 CR 4 (17) — 4 (20)
VGPR 12 (27) 1 8 3 VGPR 4 (17) 8 (40) 13 (65)
PR 22 (50) 8 13 1 PR 12 (50) 10 (50) 1 (5)
Overall ($PR) 42 (95) 10 25 7 Overall ($PR) 22 (92) 20 (100) 20 (100)
NR 2 (5) 2 — — NR 2 (8) — —

CR indicates complete response; PR, partial response; NR, no response; ASCT indicates autologous stem cell transplant; CR, complete re-
sCR, stringent CR; VMP, short-course bortezomib, melphalan, predni- sponse; PR, partial response; NR, no response; VMP, short-course
sone; VGPR, very good partial response. bortezomib, melphalan, prednisone; sCR, stringent CR; VGPR, very
*Response was evaluated according to the IMWG Criteria [20]. good partial response.
74 C. Gasparetto et al.
were identical in both groups, at 19.8 months (95%
confidence interval [CI]: 14.3, not estimable [NE]) in
non-ASCT and 27.9 months (95% CI: 14.6, NE) in
ASCT patients (Figure 1A and B). Seven patients
have died, 5 in the non-ASCT and 2 in the ASCT
group; 1-year survival rates were 82% (95% CI: 59,
93) in the non-ASCT and 95% (95% CI: 69, 99) in
the ASCT group, respectively.
Safety
The most common AEs reported during VMP
therapy in all 45 patients are shown in Table 4. Periph-
eral neuropathy grade 2-4 was the most common non-
hematopoietic side effect occurring 17 patients (38%),
although it was typically reversible and only 5 patients
(11%) discontinued therapy as a result of it. The most
common nonneurologic grade 3/4 AEs were thrombo-
cytopenia (8, 18%), neutropenia (7, 16%), and infec-
tion (5, 11%). Deep-vein thrombosis was reported in
1 (2%) patient. Additionally, 1 patient with a history
of severe peripheral vascular disease experienced wors-
ening symptoms while receiving therapy, but with no
evidence of occlusion; no intervention was necessary.
Eight (18%) patients discontinued treatment because
of AEs, including peripheral neuropathy in 5 (11%),
severe orthostatic hypotension, sustained grade .3
pancytopenia, and pneumonia each in 1 (2%) patient.
Bortezomib dose reductions were required in 7
(16%) patients because of peripheral neuropathy,
including 1 patient in cycle 2, 2 in cycle 3, and 4 in
cycle 4. Seven patients have died, 6 from disease pro-
gression plus the patient who discontinued because
of pneumonia.
DISCUSSION
The results of our phase II study indicate that
short-course VMP represents a highly effective induc-
tion therapy prior to ASCT for previously untreated
MM patients. The rate of equal to or more than CR,
the primary end point of the study, was 18%, including
9% sCR, whereas overall, 45% of patients achieved
equal to or more than VGPR to VMP. Among patients
who proceeded to transplant, the notable responses to
VMP induction translated into very high post-ASCT
response rates, including 30% equal to or more than
CR and 95% equal to or more than VGPR, which
appear to compare favorably with other studies of
bortezomib-based induction regimens [6-8]. Because
achievement of CR/VGPR is associated with im-
proved long-term outcomes [5], the high response
rates seen in our study are important, and the prelim-
inary outcome data reported herein appear promising
in both ASCT and non-ASCT patients. However,
longer follow-up beyond the current median of
approximately 14 months is required.
Biol Blood Marrow Transplant 16:70-77, 2010
As this was not a randomized study, strong conclu-
sions cannot be drawn from comparisons of outcomes
among ASCT and non-ASCT patients. Randomized
phase III studies, with lengthy follow-up, comparing
VMP alone with VMP induction plus ASCT would
be required to determine whether consolidation with
ASCT provides additional benefit in terms of long-
term outcomes. Indeed, because many centers no lon-
ger have an upper age limit for ASCT eligibility, and
transplant-related mortality has been reduced to
\2%, it may be reasonable to consider comparing
VMP plus ASCT with other induction-plus-transplant
strategies as well as with nontransplant multiagent
approaches such as lenalidomide plus dexamethasone
and other combinations. An important consideration
in these studies will be to carefully monitor patients
during long-term follow-up, because any advantages
in terms of outcomes may become evident only after
an extended period of time.
VMP therapy was well tolerated by the majority of
patients; toxicities were predictable and generally
manageable, and did not include any unexpected
AEs. The safety profile was in line with previous expe-
rience with this regimen [15,16,22] and with bortezo-
mib [23] and MP [22,24,25]. Although only 20 of 45
patients proceeded to ASCT, this was primarily
because of patient and physician choice regarding
treatment options and was not related to excessive
toxicity with VMP. Although Mel-based therapy is
typically avoided prior to transplant because pro-
longed exposure to Mel can adversely affect stem cell
collection [17], we observed no difficulties in collect-
ing stem cells from VMP-treated patients, nor any
delays in engraftment following transplant. This was
presumably because VMP was given for only a rela-
tively short time prior to stem cell collection; however,
the possibility that VMP induction could result in stem
cell collection problems in a minority of patients can-
not be excluded based on results from this relatively
small study.
Our results with short-course VMP in non-ASCT
patients suggest that this regimen may be worth fur-
ther investigation in the transplant-ineligible popula-
tion. At 24 weeks, the planned duration of VMP
treatment in the present study was shorter than in
the VISTA phase III (54 weeks) [22,26] and previous
phase I/II (49 weeks) [15,16] studies, which used
more intense dosing of bortezomib for the first 24
weeks (twice weekly for 2 of every 3 weeks), and similar
to that in a recently reported Spanish Myeloma Group
phase III study of reduced-intensity VMP in trans-
plant-ineligible elderly MM patients (31 weeks; 6
weeks of bortezomib twice weekly for 2 of every 3
weeks, then 25 weeks of weekly bortezomib for 4 of
every 5 weeks) [27]. Our overall response rate among
all 45 patients of 95% appears favorable in relation
to the response rates of 71% [22,26], 89% [15,16],
Biol Blood Marrow Transplant 16:70-77, 2010 VMP Therapy in Frontline MM Patients Eligible/Ineligible for ASCT 75

Figure 1. (A) Time to progression, (B) progression-free survival, and (C) overall survival among all patients receiving VMP, according to transplant
status.
76 C. Gasparetto et al.
Table 4. Most Common Adverse Events in Patients Receiving
VMP (N545)
Adverse event Grade 2 Grade 3/4
Peripheral neuropathy 9 (20) 10 (22)
Thrombocytopenia 4 (9) 8 (18)
Neutropenia 5 (11) 7 (16)
Infection 4 (9) 5* (11)
Gastrointestinal 5 (11) 2 (4)
Deep vein thrombosis 0 1 (2)
Orthostatic hypotension 0 1 (2)
Fatigue 6 (13) 0 4. Blade J, Rosinol L, Sureda A, et al. High-dose therapy intensifica-
Skin rash 2 (4) 0 tion compared with continued standard chemotherapy in multiple
*One death.
and 81% [28] in the above 3 studies, respectively,
although our CR rate (18%) and that in the study of re-
duced-intensity VMP (22%) [27] appear lower than in
VISTA (30%) [22,26] and the phase I/II study (32%)
[15,16]. As in these other studies [15,16.22,26,27] re-
sponses to VMP in the present study were rapid,
with 83% of responders achieving their best response
by the end of cycle 4. The higher CR rates in the
VISTA and phase I/II studies may be because of pro-
longed courses of VMP improving quality of response
in a proportion of patients [15,28]. However, pro-
longed therapy may be associated with continued tox-
icity in some patients (although the latter 30 weeks of
VMP therapy in VISTA, which used weekly bortezo-
mib dosing for 2 of every 3 weeks, was associated
with lower rates of grade 3/4 AEs compared with the
first 24 weeks [26]), as well as the inconvenience of at-
tending frequent hospital appointments for a long pe-
riod of time. Therefore, our short-course VMP
therapy and the reduced-intensity regimen being stud-
ied in the Spanish phase III study may represent highly
active but more tolerable and convenient treatment
options for some patients. Randomized studies of dif-
ferent VMP schedules with long-term follow-up
would be required to assess the relative risks and ben-
efits of each approach.
In conclusion, this study demonstrates that a short
course of modified VMP therapy represents a highly
effective and well-tolerated therapy for previously
untreated MM patients, both as initial treatment in
non-ASCT patients and as induction in patients pro-
ceeding to transplant, with rapid responses and high
response rates. Longer follow-up and prospective
phase III trials are required to validate these initial ob-
servations.
ACKNOWLEDGMENTS
Financial disclosure: The authors thank Steve Hill
and Jane Saunders for editorial assistance in the prep-
aration of the manuscript. Steve Hill is a medical
writer, and Jane Saunders a medical editor with
Gardiner-Caldwell London.
Biol Blood Marrow Transplant 16:70-77, 2010
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