Successful mobilization of PBSCs predicts favorable outcomes in

Bone Marrow Transplantation (2015) 50, 673–678
© 2015 Macmillan Publishers Limited All rights reserved 0268-3369/15
www.nature.com/bmt
ORIGINAL ARTICLE
Successful mobilization of PBSCs predicts favorable outcomes
in multiple myeloma patients treated with novel agents and
autologous transplantation
A Brioli1,12, G Perrone2,12, F Patriarca3, A Pezzi1, F Nobile4, F Ballerini5, MR Motta1, S Ronconi6, P Tacchetti1, L Catalano7, BA Zannetti1,
S Rizzi1, S Volpe8, E Zamagni1, AM Liberati9, K Mancuso1, M Boccadoro10, FE Davies11, GJ Morgan11, A Palumbo10 and M Cavo1
Incorporation of novel agents into auto-SCT for patients with multiple myeloma has led to improvement in their outcomes.
However, the effects of new drugs, either single or combined, on PBSC mobilization have not been fully evaluated, particularly in
phase 3 clinical studies. We analyzed the impact of two novel agent-based induction treatments in patients enrolled in the GIMEMA
MMY-3006 study comparing bortezomib, thalidomide and dexamethasone (VTD) versus thalidomide and dexamethasone (TD) in
preparation for double auto-SCT. Results showed that a short-term induction therapy with VTD did not adversely affect CD34+ cell
yields as compared with TD (9.75 vs 10.76 × 106 CD34+ cells/kg, P = 0.220). For poor mobilizers (o4 × 106 CD34+ cells/kg), 5-year
rates of time to progression (TTP), progression-free survival (PFS) and overall survival (OS) were significantly shorter than for
successful mobilizers (TTP:17 vs 48%, P o0.0001; PFS: 16 vs 46%, P o 0.0001; OS: 50 vs 80%, P o 0.0001). These differences were
retained across patients randomized to the TD arm; conversely, no differences in outcomes were seen in patients treated with VTD,
irrespective of the number of harvested CD34+ cells. The number of collected PBSCs predicted better outcomes after auto-SCT and
VTD overcame the negative impact of a poor stem cell mobilization.
Bone Marrow Transplantation (2015) 50, 673–678; doi:10.1038/bmt.2014.322; published online 2 February 2015
INTRODUCTION
High dose chemotherapy (HDT) with auto-SCT is considered the
standard of care for young and fit patients with newly diagnosed
multiple myeloma (MM).1 Compared with conventional chemotherapy, newer doublet regimens incorporating either the
immunomodulatory drug thalidomide or the first-in-class proteasome inhibitor bortezomib in combination with dexamethasone
have increased the rate of high-quality responses before autoSCT.2,3 More recently, we and other groups have shown that the
triplet combination of bortezomib, thalidomide and dexamethasone (VTD) is superior to two-drug regimens including
thalidomide and dexamethasone (TD) or bortezomib and dexamethasone (VD) in terms of enhanced rates of CR and very good
PR, a gain translating into prolonged PFS.4–6 However, the effects
of these new drugs on CD34+ hematopoietic stem cells and the
niches in which they reside have not been specifically evaluated,
particularly in phase 3 clinical studies. Conflicting data, which
need to be addressed, exist about the possible interference of
some of these drugs, including structurally different agents that
belong to the same pharmacological class on PBSC harvest.
Although in several studies the total counts of CD34+ stem cells
collected after prior exposure to TD or triplet thalidomide-based
regimens were lower in comparison with conventional
chemotherapy,2,7 it is likely that this negative effect, if any, is of
little clinical relevance and doesn’t impact patients’ ability to
receive auto-SCT.2 Unlike thalidomide, lenalidomide is toxic to
normal hematopoietic stem cells and suppresses their motility, an
effect which, combined with the antiangiogenic properties of the
drug, can adversely impair PBSC harvest, particularly after a
relatively long treatment duration.8,9 VD as induction therapy did
not negatively affect PBSC mobilization.10 However, when
bortezomib at a reduced dose was added to thalidomide and
dexamethasone, a significantly lower number of collected CD34+
cells was reported in comparison with VD.5 Similarly, a three-drug
combination including CY, thalidomide and dexamethasone was
associated with mobilization failure in about 25% of the patients,11
and subjects who received induction therapy with thalidomide,
doxorubicin and dexamethasone were reported to have a
significantly lower median CD34+ cell yield compared with
patients receiving standard chemotherapy.12 Although these
results might suggest that triplet induction regimens including
one or two of the novel agents thalidomide and bortezomib may
be associated with an increased risk for impaired PBSC procurement, conclusive data have not been reported so far. To address
1
Istituto di Ematologia Seràgnoli, Università degli Studi di Bologna, Policlinico Sant'Orsola-Malpighi, Bologna, Italy; 2Hematology Department, Fondazione IRCCS Istituto Nazionale
dei Tumori, Milano, Italy; 3Department of Hematology, Stem Cell Transplant Unit, DISM, University Hospital, Udine, Italy; 4Hematology Unit, Azienda Ospedaliera Bianchi Melacrino
Morelli, Reggio Calabria, Italy; 5Department of Hematology and Oncology, IRCCS AOU San Martino-IST, Genova, Italy; 6Department of Hematology, Istituto Scientifico Romagnolo
per Studio e Cura dei Tumori, Meldola, Italy; 7Divisione di Ematologia, Università Federico II, Napoli, Italy; 8Division of Onco-Hematology, S.G. Moscati Hospital, Avellino, Italy;
9
Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Perugia, Struttura Complessa Oncoematologia con autotrapianto, Azienda Ospedaliera Santa Maria,
Terni, Italy; 10Division of Hematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy and 11Myeloma Institute for Research and
Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA. Correspondence: Professor M Cavo, Istituto di Ematologia Seràgnoli, Università degli Studi di Bologna,
Policlinico Sant'Orsola-Malpighi, Via Massarenti 9, Bologna 40138, Italy.
E-mail: [email protected]
12
These authors contributed equally to the work.
Received 18 August 2014; revised 29 November 2014; accepted 2 December 2014; published online 2 February 2015
Stem cell harvest and novel agents
A Brioli et al
674
this issue, we analyzed the impact of induction treatment with
either VTD or TD on PBSC collection, which was a secondary
endpoint of the GIMEMA MMY-3006 study.
MATERIALS AND METHODS
The GIMEMA MMY-3006 study (NCT01134484) was a phase 3 open-label,
multicentre trial aimed to assess the efficacy and safety of VTD versus TD
as induction therapy in preparation for double auto-SCT in newly
diagnosed MM. The design, objectives and main results of the study have
previously been reported.4,13 In brief, after three 21-day cycles of VTD or TD
induction therapy, all patients were to receive a single dose of CY (ID-CTX)
at 4 g/m2, followed by G-CSF 10 µg/kg/day starting from day 2 after ID-CTX
until the last day of leukapheresis. Study protocol was designed to perform
a double auto-SCT with high-dose melphalan 200 mg/m2 and the target
threshold was set at 4 × 106 CD34+ cells/kg. Patients who failed to achieve
the threshold dose were allowed to undergo an additional collection of
PBSCs either with high-dose G-CSF alone (20 µg/kg) or BM withdrawal.
Patients who yielded o 4 × 106 CD34+ cells/kg could continue study
protocol provided that their CD34+ count was ⩾ 2 × 106/kg to support a
single course of high-dose melphalan. Protocol design and patient flow
chart between ID-CTX and auto-SCT are summarized in Figure 1.
Primary study endpoint was the rate of CR and near CR after VTD or TD
induction therapy. Safety and toxicity of the triplet and doublet induction
regimens, including PBSC collection, was a secondary study endpoint, and
was specifically addressed in this sub-analysis. Continuous data were
expressed as median with inter quartile range (IQR) and were assessed by
Kolmogorov–Smirnov test or Wilcoxon–Mann–Whitney test, as appropriate. Discrete data were expressed as frequencies and percentages and
were assessed by the χ2-test or Fisher's exact test, as appropriate. The
Kaplan–Meier method was used to estimate time to progression (TTP), PFS
and OS, while curves were compared using the log-rank test. A multivariate
Cox regression analysis was done to identify independent factors
associated with TTP, PFS and OS. Statistical analyses were performed
using Stata v.11 (Stata Statistical Software, StataCorp, College Station, TX,
USA) and statistical significance was set at P o0.05.
RESULTS
The study enrolled 480 patients, of which 435 (223 randomized to
the VTD arm and 212 to the TD arm) received ID-CTX to mobilize
PBSCs and formed the basis of the present analysis.
Baseline characteristics of the 435 patients are reported in
Table 1. Rates of high-quality responses were significantly higher
VTD arm
in the VTD arm, with 32% and 63% of patients achieving at least
near CR and very good PR compared with 13% (P o 0.001)
and 31% (P o 0.001) of those randomized to TD, respectively.
The two treatment groups were comparable with respect
to the time elapsing between the start of induction and the
mobilization phase.
Table 1.
Patient characteristics at baseline
Age (years)
Median age (IQR)
All pts
(n = 435)
VTD
(n = 223)
TD
(n = 212)
57 (52–62)
58 (52–62)
57 (52–62)
Sex, n (%)
Male
253 (58)
131 (59)
122 (58)
Myeloma isotype, n (%)
IgG
IgA
Other
277 (64)
84 (19)
74 (17)
145 (66)
39 (17)
39 (17)
132 (62)
45 (21)
35 (17)
ISS stage, n (%)
1
2
3
204 (47)
161 (37)
70 (16)
104 (47)
83 (37)
36 (16)
100 (47)
78 (37)
34 (16)
BM plasma cells, n (%)
Median (IQR)
50 (30–70)
50 (31–70)
FISH analysis for cytogenetic abnormalities, n (%)
Absence of del(13q),t(4;14) 188 (47)
91 (41)
and del(17p)
Presence of del(13q)
189 (47)
100 (45)
Presence of t(4;14) and/or 101 (25)
52 (22)
del(17p)
Not evaluable
33 (7)
18 (8)
50 (30–70)
97 (46)
89 (42)
49 (23)
15 (7)
Abbreviations: ISS = international staging system; IQR = interquartile range;
TD = thalidomide and dexamethasone; VTD = bortezomib with thalidomide plus dexamethasone.
TD arm
223 pts received ID-CTX
212 pts received ID-CTX
4 patients discontinued
during mobilization:
1 lost at FU
3 inadequate stem
cell collection
219 pts completed mobilization
7 patients discontinued
after mobilization or
during ASCT:
5 toxic effect
2 death
212 pts completed first ASCT
5 patients discontinued
during mobilization:
2 toxic effect
1 inadequate stem
cell collection
1 withdrew consent
1 death
207 pts completed mobilization
11 patients discontinued
after mobilization or
during ASCT
4 disease progression
4 toxic effect
2 death
1 allogeneic
transplantation
196 pts completed first ASCT
VTD: bortezomib with thalidomide plus dexamethasone; TD: thalidomide plus dexamethasone; pts: patients;
ID-CTX: cyclophosphamide 4 g/m2; ASCT: autologous stem cell transplantation
Figure 1.
Trial work-flow of mobilization phase.
Bone Marrow Transplantation (2015) 673 – 678
© 2015 Macmillan Publishers Limited
Stem cell harvest and novel agents
A Brioli et al
The median number of collected CD34+ cells was 9.75 × 106/kg
in the VTD arm and 10.76 × 106/kg in the TD arm (P = 0.220;
Supplementary Table 1). A harvest of 410 × 106 CD34+ cells/kg
was yielded in 50% (n = 110) and 58% (n = 123) of VTD- and TDtreated patients (P = 0.228), respectively, and identified the socalled subgroup of excellent mobilizers. Only 13 patients (6%) in
the VTD group and 15 patients (7%) in the TD group failed to yield
the threshold dose of 4 × 106 CD34+ cells/kg, and were classified
as poor mobilizers; 5 patients in each treatment arm yielded
o2 × 106 CD34+ cells/kg and were referred to as unsuccessful
mobilizers. In both treatment arms, the target threshold was
achieved after the first mobilization in 91% of patients (P = 0.867).
Of these, almost half underwent a single leukapheresis
(Supplementary Table 1).
A second mobilization was performed in 31 patients (18 in VTD
and 13 in TD, P = 0.432), of which 27 were mobilized with
G-SCF alone.
ID-CTX was well-tolerated and no treatment-related death was
registered. A single patient died suddenly 30 days after CD34+ cell
collection, but the death was considered not related to study
drugs or mobilization procedure by treating physicians. ID-CTX
was received by the majority of the patients (86% in VTD and 82%
in TD, P = 0.251) as an in-patient procedure, with a median time of
hospitalization of 4 days. Hematologic toxicity and transfusion
requirements were comparable between the two treatment arms,
as was the occurrence of grade 3–4 infective complications (2% in
VTD vs 3% in TD) (Supplementary Table 2).
Of the 426 patients who completed mobilization, 218 in the VTD
group and 201 in the TD group subsequently proceeded to autoSCT (Figure 1). One patient in the VTD arm discontinued study
protocol due to toxicity. In the TD arm, six patients discontinued
due to toxicity (four patients) or disease progression (two
patients).
After the first course of high-dose melphalan a median number
of 4 × 106 and of 4.5 × 106 CD34+ cells/kg were infused in patients
randomized to the VTD and TD arms, respectively (P = 0.01). No
differences were seen between the two groups regarding
hematologic recovery, with the only exception of the median
time to platelet engraftment (that is, 420 000/mm3), which was
slightly longer in the VTD group (12 vs 11 days, P = 0.002). Nonhematologic toxicity was comparable between the two arms.
An univariate analysis of patient-, disease- and response-related
variables potentially predictive for a successful PBSC mobilization
revealed a significant relationship between the presence at
baseline of both ISS stage 1–2 (P = 0.004) and Hb410.5 g/dL
(P = 0.008) and a CD34+ cell harvest ⩾ 4 × 106/kg (Table 2).
Achievement of CR and near CR after induction treatment
(P = 0.013) was an additional prognosticator for successful PBSC
yield. These variables well-predicted for the probability of
collecting between 4 and 10 × 106 CD34+ cells/kg or ⩾ 10 × 106
CD34+ cells/kg, confirming that the subgroups of ‘good’ and
‘excellent’ mobilizers could be pooled together. Conversely, age,
platelets, C-reactive protein, cytogenetic abnormalities and BM
plasma cell infiltration before harvest did not show any significant
relationship on CD34+ cells yield.
When the analysis was performed according to treatment arm
randomization, none of the above mentioned variables predicted
for successful CD34+ cell harvest in patients randomized to receive
VTD. By the opposite, both ISS stage and Hb concentration
retained their predictive value for successful PBSC collection in the
TD arm of the study.
With a median follow-up of 66 months, Kaplan–Meier analyses
showed that 5-year estimates for TTP (17 vs 48%, P o 0.0001), PFS
(16 vs 46%, P o 0.0001) and OS (50 vs 80%, P o 0.0001) were
significantly shorter for patients yielding o 4 × 106 CD34+/kg
compared with those with a harvest ⩾ 4 × 106 CD34+/kg
(Figures 2a–c). No statistically significant differences in clinical
outcomes were found between good and excellent mobilizers.
© 2015 Macmillan Publishers Limited
675
Table 2.
+
Univariate analysis of variables predictive for CD34 cell
harvests
CD34+ cells
o4 × 106/kg
(28 pts)
Ageo60 years
Hb ⩾ 10.5 g/dL
Plts ⩾ 150 000/mm3
Creatinine ⩽ 1.2 mg/dL
C-reactive proteino 0.6 mg/dL
ISS 1–2
BM PCo30% before CD34+
collection
Absence of del(13q),
t(4;14) and del(17p)
Presence of del(13q)
Presence of t(4;14) and/or
del(17p)
⩾ nCR to induction therapy
16
11
24
21
16
18
27
(57%)
(39%)
(86%)
(68%)
(56%)
(64%)
(92%)
CD34+ cells
⩾ 4 × 106/kg
(407 pts)
263
262
369
324
211
347
395
(65%)
(64%)
(91%)
(80%)
(44%)
(85%)
(96%)
P
0.43
0.008
0.39
0.14
0.25
0.004
0.50
14 (54%)
174 (46%)
0.46
12 (46%)
7 (27%)
176 (47%)
94 (25%)
0.94
0.83
1 (4%)
97 (24%)
0.013
Abbreviations: ISS = international staging system; nCR = near complete
remission; PC = plasma cells.
This finding provided further support to the conclusion that in our
analysis patients achieving the threshold dose of 4 × 106 CD34+
cells/kg could be considered as a single prognostic group.
Patients who were randomized to receive VTD induction
therapy had similar TTP (P = 0.3282), PFS (P = 0.2418) and OS
(P = 0.8580) curves (Supplementary Figures 1A–C) irrespective of
the number of collected CD34+ cells (that is, o4 vs ⩾ 4 × 106
CD34+/kg). In the group of patients randomized to TD, those who
were classified as ‘poor’ and ‘unsuccessful’ mobilizers had a
significantly shorter TTP (P o0.0001), PFS (P o0.0001) and OS
(P o 0.0001) compared with those who were classified as ‘good’
and ‘excellent’ mobilizers (Supplementary Figures 2A–C).
In a multivariate Cox regression analysis, a yield of CD34+ cells
⩾ 4 × 106/kg was an independent variable significantly related to
extended TTP, PFS and OS (Table 3). Additional favorable
prognostic variables included randomization to the VTD arm, the
absence of del(17q) and/or t(4;14), beta2-microglobulin levels
o3.5 mg/dL and the attainment of best CR/near CR (Table 3).
When double auto-SCT was entered into the model, no significant
relationship was found with clinical outcomes; conversely, the
number of collected CD34+ cells retained prognostic value
(P = 0.001). Similar results were obtained when the number of
transplant(s) actually received was replaced by the number of
infused CD34+ cells. These data, while confirming that a harvest
⩾ 4 × 106 CD34+ cells/kg was associated with a higher number of
infused CD34+ cells (median 4.4 (IQR 3.4–5.5) vs 2.3 (IQR 1.8–3.7)
CD34+ × 106/kg in the subgroups of ‘successful’ and ‘poor’
mobilizers, respectively) and with 470% probability of delivering
double auto-SCT, suggest that PBSC yield was per se predictive for
an improved outcome.
DISCUSSION
The optimal number of PBSCs to be collected from a patient who
is eligible to receive an auto-SCT still remains a critical issue. The
target is dependent from various factors, of which some are
related to the patient itself and include age, performance status,
comorbidities and the preference to receive HDT upfront or at
relapse.8 However, the number of planned auto-SCTs is the most
important factor related to the harvest. Two randomized trials
performed before the novel agent era prospectively compared a
single versus double auto-SCT. In both studies, a survival
advantage was reported with tandem auto-SCT, particularly for
Bone Marrow Transplantation (2015) 673 – 678
Stem cell harvest and novel agents
A Brioli et al
676
a
Median TTP p
1.00
0.75
CD34+<4
22 months
CD34+≥4
57 months
<0.0001
CD34+≥4
0.50
0.25
CD34+<4
0.00
Number at risk
CD34+<4
CD34+≥4
0
12
24
36
48
60
28
407
23
373
10
331
8
267
5
196
4
137
b
p
Median PFS
1.00
+
CD34 <4 22 months
CD34+≥4 55 months
0.75
<0.0001
CD34+≥4
0.50
0.25
CD34+<4
0.00
Number at risk
CD34+<4
CD34+≥4
c
0
12
24
36
48
60
28
407
23
373
10
331
8
267
5
196
4
137
1.00
CD34+≥4
0.75
0.50
CD34+<4
OS @ 5 years
p
0.25
0.00
Number at risk
CD34+<4
CD34+≥4
Figure 2.
CD34+<4
50%
CD34+≥4
80%
<0.0001
0
12
24
36
48
60
28
407
23
380
20
361
17
342
14
288
9
224
Kaplan–Meier curves according to the number of stem cell harvested. (a) TTP; (b) PFS; (c) OS.
those patients who failed at least near CR or very good PR after
the first auto-SCT.14,15 This observation has increased the number
of tandem auto-SCT offered to patients with a suboptimal
response to the first course of HDT. In addition, a second autoSCT can also be effectively administered as salvage therapy at the
time of relapse after the first auto-SCT, especially to patients with a
sustained remission between the first and second auto-SCT.16,17
Therefore, in the current era, it is of primary importance to collect
an appropriate number of hematopoietic stem cells and to
carefully investigate the possible interference of new drugs with
PBSC mobilization. In this sub-analysis of the GIMEMA MMY-3006
study, we analyzed the impact of a three-drug induction therapy
including the two novel agents bortezomib and thalidomide
versus TD on the ability to collect stem cells. We demonstrated
that a short-term induction therapy with VTD did not adversely
affect CD34+ cell harvest compared with TD. More than 90% of
Bone Marrow Transplantation (2015) 673 – 678
VTD-treated patients achieved the target value of 4 × 106 CD34+
cells/kg and more than half of patients collected a number of
CD34+ cells 410 × 106/kg. Therefore, differently from several prior
reports,5,10 the triplet combination of TD with bortezomib was
associated with a high rate of successful stem cell yield.
We hypothesized that the low incidence of collection failure
observed in our study could be due, at least in part, to the use of a
mobilization strategy including ID-CTX. The capability of CY to
produce rebound CD34+ cell spillover into the blood during the
recovery phase after chemotherapy-induced cytopenia has long
been known.18 It has also been reported that ID-CTX and G-CSF
allow for a more rapid stem cell collection and higher number of
harvested CD34+ cells compared with G-CSF alone.18,19 However,
concerns on the increased rate of infectious complications
following the use of ID-CTX have been raised and some studies
have also shown a longer timing to engraftment after HDT and
© 2015 Macmillan Publishers Limited
Stem cell harvest and novel agents
A Brioli et al
Table 3. Multivariate analysis of variables predictive for favorable
outcomes after auto-SCT
HR
CI
P
TTP
CD34+ cells ⩾ 4 × 106/kg
VTD therapy
Absence del(17p) and t(4;14)
Beta2o3.5 mg/dL
Best ⩾ nCR
0.34
0.60
0.43
0.55
0.69
0.20–0.56
0.45–0.79
0.32–0.57
0.42–0.73
0.52–0.91
o0.001
o0.001
o0.001
o0.001
0.009
PFS
CD34+ cells ⩾ 4 × 106/kg
VTD therapy
Absence del(17p) and t(4;14)
Beta2o3.5 mg/dL
Best ⩾ nCR
0.35
0.63
0.46
0.54
0.65
0.21–0.56
0.48–0.82
0.35–0.61
0.41–0.71
0.50–0.86
o0.001
0.001
o0.001
o0.001
0.002
OS
CD34+ cells ⩾ 4 × 106/kg
Absence del(17p) and t(4;14)
Beta2o3.5 mg/dL
Best ⩾ nCR
0.26
0.46
0.36
0.60
0.15–0.45
0.31–0.69
0.24–0.54
0.40–0.90
o0.001
o0.001
o0.001
0.013
Abbreviations:
Beta2 = beta2-microglobulin;
nCR = near
complete
response; TTP = time to progression; VTD = bortezomib, thalidomide and
dexamethasone.
auto-SCT.20 Results from the present analysis do not confirm these
data. In our patient cohort, we found a low infective morbidity,
and no delayed time to engraftment after the first auto-SCT was
observed. Although cross-trial comparisons may be inadequate,
we confirmed that ID-CTX resulted in a higher median number of
collected CD34+ cells compared with that reported with the use of
G-CSF alone after induction therapy using the triplet combination
of TD with either bortezomib or doxorubicin.5,10 Recently,
plerixafor has been introduced into the therapeutic armamentarium for PBSC mobilization. In several studies, the addition of
plerixafor to G-CSF resulted in a significant increase in the median
number of stem cells harvested in comparison with G-CSF
alone.21–24 Based on these and other results, the preemptive
administration of plerixafor in patients previously exposed to
melphalan or to more than four cycles of lenalidomide has been
suggested. Outside these cases, the optimal choice between
chemotherapy mobilization, including ID-CTX and G-CSF, and
plerixafor combined with G-CSF to maximize PBSC yield cannot be
established, due to the lack of data.25 However, adding plerixafor
to the mobilization strategy increases the cost of the procedure by
450%.
An important, not yet reported, finding of our analysis was that
a yield of CD34+ cells 44 × 106/kg was an independent
prognosticator for extended PFS, TTP and OS in the whole patient
population. We found that in the TD arm of the study, the
subgroup of ‘poor’ mobilizers (for example, collecting o 4 × 106
CD34+ cells/kg) had a significantly shorter PFS, TTP and OS
compared with the successful mobilizer subgroup. This difference
was not seen in the VTD arm of the study, suggesting that the
triplet VTD regimen as induction and consolidation therapy was
able to overcome the negative impact on prognosis of a poor
PBSC yield. Therefore, for the first time, we demonstrated that the
outcome of MM patients was influenced not only by wellrecognized disease- and treatment response-related factors, but
also by a new biological variable, such as the number of harvested
CD34+ cells. In this context, we hypothesized that a successful
PBSC mobilization might reflect a more permissive BM milieu, an
hypothesis further supported by the correlation between CD34+
cell yields and achievement of best CR/near CR (43% for patients
with o 4 × 106 CD34+ cells/kg vs 70% for patients with ⩾ 4 × 106
© 2015 Macmillan Publishers Limited
CD34+ cells/kg, P = 0.003). To further verify this hypothesis, we
evaluated whether the positive impact on prognosis of a
successful PBSC mobilization was related to the number of autoSCT(s) performed or to the number of infused CD34+ cells.
Although this relationship was confirmed, as logically expected,
the outcome of good mobilizers was not influenced by the
number of infused CD34+ cells (data not shown), supporting the
hypothesis that a successful PBSC mobilization is a surrogate
marker for a better outcome. These findings were also strengthened by the multivariate analyses, in which the more powerful
model was the one including the number of harvested CD34+ cells
as compared with that of infused CD34+ cells or to the number of
transplant(s) received.
One limitation of the present study is that it was not designed
to evaluate the BM microenvironment, and therefore no biological
data on stromal cells are available. The lack of prognostic
relevance of collected CD34+ cells in the VTD arm of the study
may be a limitation of the efficiency of this new biomarker in a
population of patients receiving this triplet induction therapy.
However, the finding that bortezomib combined with thalidomide
and dexamethasone is able to overcome the negative prognostic
effect of a poor mobilization is an important notion, which might
help clinicians to select the optimal treatment among the many so
far available for newly diagnosed MM patients.
In conclusion, a short-term induction therapy containing two
novel drugs such as bortezomib and thalidomide does not impair
stem cell harvest in MM patients. The number of collected CD34+
cells has emerged as a novel and independent variable predictive
for favorable outcome after auto-SCT.
CONFLICT OF INTEREST
AB has received honoraria from Celgene, MC has received honoraria and served on
speakers’ bureaux for Janssen-Cilag, Millennium Pharmaceuticals, Celgene and
Novartis and has been a consultant for Janssen-Cilag and Millennium
Pharmaceuticals. FP has received honoraria from Janssen-Cilag, Celgene, ScheringPlough and Roche; AP has served on an advisory committee for Celgene, JanssenCilag, Amgen, Bristol-Myers Squibb, Millenium and Onyx and has received honoraria
from Celgene, Janssen-Cilag, Bristol-Myers Squibb, Millenium, Onyx and Amgen; MB
has received honoraria from Novartis and Bristol-Myers Squibb. The remaining
authors declare no conflict of interest.
ACKNOWLEDGEMENTS
This study was funded and sponsored by the Seràgnoli Institute of Hematology at the
University of Bologna, Bologna, Italy. The study was partly supported by Janssen
providing bortezomib free of charge, by the University of Bologna through a grant to
MC (Ricerca Fondamentale Orientata), and by BolognaAIL. FED is a Cancer Research
UK Senior Clinical Fellow.
AUTHOR CONTRIBUTIONS
MC was the principal investigator and takes primary responsibility for the paper;
AB, GP and MC designed the research and wrote the paper; AB, GP and APe
performed the analysis; FP, FN, FB, SR, LC, SV, AML, MB and APa were the
subinvestigators of the study and recruited the patients; PT, BAZ, EZ and KM
provided patients and collected the data; MRM and SR performed cell
laboratory work and collected the data; FED and GJM provided important
intellectual inputs.
REFERENCES
1 Cavo M, Rajkumar SV, Palumbo A, Moreau P, Orlowski R, Blade J et al. International
Myeloma Working Group consensus approach to the treatment of multiple
myeloma patients who are candidates for autologous stem cell transplantation.
Blood 2011; 117: 6063–6073.
2 Cavo M, Zamagni E, Tosi P, Tacchetti P, Cellini C, Cangini D et al. Superiority of
thalidomide and dexamethasone over vincristine-doxorubicindexamethasone
(VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood 2005; 106: 35–39.
Bone Marrow Transplantation (2015) 673 – 678
677
Stem cell harvest and novel agents
A Brioli et al
678
3 Harousseau JL, Attal M, Avet-Loiseau H, Marit G, Caillot D, Mohty M et al.
Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin
plus dexamethasone as induction treatment prior to autologous stem-cell
transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01
phase III trial. J Clin Oncol 2010; 28: 4621–4629.
4 Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M et al. Bortezomib
with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double
autologous stem-cell transplantation in newly diagnosed multiple myeloma: a
randomised phase 3 study. Lancet 2010; 376: 2075–2085.
5 Moreau P, Avet-Loiseau H, Facon T, Attal M, Tiab M, Hulin C et al. Bortezomib plus
dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation
in newly diagnosed multiple myeloma. Blood 2011; 118: 5752–5758.
6 Rosinol L, Oriol A, Teruel AI, Hernandez D, Lopez-Jimenez J, de la Rubia J et al.
Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction
pretransplantation therapy in multiple myeloma: a randomized phase 3
PETHEMA/GEM study. Blood 2012; 120: 1589–1596.
7 Breitkreutz I, Lokhorst HM, Raab MS, Holt B, Cremer FW, Herrmann D et al. Thalidomide in newly diagnosed multiple myeloma: influence of thalidomide treatment on peripheral blood stem cell collection yield. Leukemia 2007; 21:
1294–1299.
8 Kumar S, Giralt S, Stadtmauer EA, Harousseau JL, Palumbo A, Bensinger W et al.
Mobilization in myeloma revisited: IMWG consensus perspectives on stem cell
collection following initial therapy with thalidomide-, lenalidomide-, or
bortezomib-containing regimens. Blood 2009; 114: 1729–1735.
9 Kumar S, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Gastineau DA et al. Impact
of lenalidomide therapy on stem cell mobilization and engraftment postperipheral blood stem cell transplantation in patients with newly diagnosed
myeloma. Leukemia 2007; 21: 2035–2042.
10 Moreau P, Hulin C, Marit G, Caillot D, Facon T, Lenain P et al. Stem cell collection in
patients with de novo multiple myeloma treated with the combination of bortezomib and dexamethasone before autologous stem cell transplantation
according to IFM 2005-01 trial. Leukemia 2010; 24: 1233–1235.
11 Auner HW, Mazzarella L, Cook L, Szydlo R, Saltarelli F, Pavlu J et al. High rate of
stem cell mobilization failure after thalidomide and oral cyclophosphamide
induction therapy for multiple myeloma. Bone Marrow Transplant 2011; 46:
364–367.
12 Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S,
van Oers MH et al. A randomized phase 3 study on the effect of thalidomide
combined with adriamycin, dexamethasone, and high-dose melphalan, followed
by thalidomide maintenance in patients with multiple myeloma. Blood 2010; 115:
1113–1120.
13 Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D
et al. Bortezomib-thalidomide-dexamethasone is superior to thalidomidedexamethasone as consolidation therapy after autologous hematopoietic stem
cell transplantation in patients with newly diagnosed multiple myeloma. Blood
2012; 120: 9–19.
14 Cavo M, Tosi P, Zamagni E, Cellini C, Tacchetti P, Patriarca F et al. Prospective,
randomized study of single compared with double autologous stem-cell
15
16
17
18
19
20
21
22
23
24
25
transplantation for multiple myeloma: Bologna 96 clinical study. J Clin Oncol 2007;
25: 2434–2441.
Attal M, Harousseau JL, Facon T, Guilhot F, Doyen C, Fuzibet JG et al. Single versus
double autologous stem-cell transplantation for multiple myeloma. N Engl J Med
2003; 349: 2495–2502.
Michaelis LC, Saad A, Zhong X, Le-Rademacher J, Freytes CO, Marks DI et al.
Salvage second hematopoietic cell transplantation in myeloma. Biol Blood Marrow
Transplant 2013; 19: 760–766.
Cook G, Williams C, Brown JM, Cairns DA, Cavenagh J, Snowden JA et al. Highdose chemotherapy plus autologous stem-cell transplantation as consolidation
therapy in patients with relapsed multiple myeloma after previous autologous
stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial. Lancet Oncol 2014; 15: 874–885.
Alegre A, Tomás J, Martínez-Chamorro C, Gil-Fernández J, Fernández-Villalta M,
Arranz R et al. Comparison of peripheral blood progenitor cell mobilization in
patients with multiple myeloma: high-dose cyclophosphamide plus GM-CSF vs
G-CSF alone. Bone Marrow Transplant 1997; 20: 211–217.
Arora M, Burns L, Barker J, Miller J, Defor T, Olujohungbe A et al. Randomized
comparison of granulocyte colony-stimulating factor versus granulocytemacrophage colony-stimulating factor plus intensive chemotherapy for peripheral blood stem cell mobilization and autologous transplantation in multiple
myeloma. Biol Blood Marrow Transplant 2004; 10: 395–404.
Gertz MA, Kumar SK, Lacy MQ, Dispenzieri A, Hayman SR, Buadi FK et al. Comparison of high-dose CY and growth factor with growth factor alone for mobilization of stem cells for transplantation in patients with multiple myeloma. Bone
Marrow Transplant 2009; 43: 619–625.
Cheng J, Schmitt M, Wuchter P, Buss EC, Witzens-Harig M, Neben K et al. Plerixafor
is effective given either preemptively or as a rescue strategy in poor stem cell
mobilizing patients with multiple myeloma. Transfusion (e-pub ahead of print 13
August 2014; doi:10.1111/trf.12813).
Auayporn PN, John FD, Richard TM, Edward AS, Ivana NM, Patrick JS et al. Plerixafor plus granulocyte colony-stimulating factor versus placebo plus granulocyte
colony-stimulating factor for mobilization of CD34+ hematopoietic stem cells in
patients with multiple myeloma and low peripheral blood CD34+ cell count:
results of a subset analysis of a randomized trial. Biol Blood Marrow Transplant
2012; 18: 1564–1572.
DiPersio JF, Stadtmauer EA, Nademanee A, Micallef INM, Stiff PJ, Kaufman JL et al.
Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem
cells for autologous stem cell transplantation in patients with multiple myeloma.
Blood 2009; 113: 5720–5726.
DiPersio JF, Micallef IN, Stiff PJ. Phase III prospective randomized double-blind
placebo-controlled trial of plerixafor plus granulocyte colony-stimulating factor
compared with placebo plus granulocyte colony-stimulating factor for autologous
stem-cell mobilization and transplantation for patients with non-Hodgkin's lymphoma.J Clin Oncol 2009; 27: 4767–4773.
Giralt S, Costa L, Schriber J, Dipersio J, Maziarz R, McCarty J et al. Optimizing
autologous stem cell mobilization strategies to improve patient outcomes: consensus guidelines and recommendations. Biol Blood Marrow Transplant 2014; 20:
295–308.
Supplementary Information accompanies this paper on Bone Marrow Transplantation website (http://www.nature.com/bmt)
Bone Marrow Transplantation (2015) 673 – 678
© 2015 Macmillan Publishers Limited

Download Report