From bloodjournal.hematologylibrary.org by guest on January 31, 2012. For personal use only.
2011 117: 6063-6073
Prepublished online March 29, 2011;
doi:10.1182/blood-2011-02-297325
International Myeloma Working Group consensus approach to the
treatment of multiple myeloma patients who are candidates for
autologous stem cell transplantation
Michele Cavo, S. Vincent Rajkumar, Antonio Palumbo, Philippe Moreau, Robert Orlowski, Joan
Bladé, Orhan Sezer, Heinz Ludwig, Meletios A. Dimopoulos, Michel Attal, Pieter Sonneveld, Mario
Boccadoro, Kenneth C. Anderson, Paul G. Richardson, William Bensinger, Hans E. Johnsen,
Nicolaus Kroeger, Gösta Gahrton, P. Leif Bergsagel, David H. Vesole, Hermann Einsele, Sundar
Jagannath, Ruben Niesvizky, Brian G. M. Durie, Jesus San Miguel and Sagar Lonial
Updated information and services can be found at:
http://bloodjournal.hematologylibrary.org/content/117/23/6063.full.html
Articles on similar topics can be found in the following Blood collections
Clinical Trials and Observations (3423 articles)
Free Research Articles (1338 articles)
Lymphoid Neoplasia (1017 articles)
Perspectives (110 articles)
Transplantation (1733 articles)
Information about reproducing this article in parts or in its entirety may be found online at:
http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#repub_requests
Information about ordering reprints may be found online at:
http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#reprints
Information about subscriptions and ASH membership may be found online at:
http://bloodjournal.hematologylibrary.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly
by the American Society of Hematology, 2021 L St, NW, Suite 900,
Washington DC 20036.
Copyright 2011 by The American Society of Hematology; all rights reserved.

---

From bloodjournal.hematologylibrary.org by guest on January 31, 2012. For personal use only.
Perspectives
International Myeloma Working Group consensus approach to the treatment of
multiple myeloma patients who are candidates for autologous stem cell
transplantation
Michele Cavo,1 S. Vincent Rajkumar,2 Antonio Palumbo,3 Philippe Moreau,4 Robert Orlowski,5 Joan Blade´,6 Orhan Sezer,7
Heinz Ludwig,8 Meletios A. Dimopoulos,9 Michel Attal,10 Pieter Sonneveld,11 Mario Boccadoro,12 Kenneth C. Anderson,13
Paul G. Richardson,13 William Bensinger,14 Hans E. Johnsen,15 Nicolaus Kroeger,16 Go¨sta Gahrton,17 P. Leif Bergsagel,18
David H. Vesole,19 Hermann Einsele,20 Sundar Jagannath,21 Ruben Niesvizky,22 Brian G. M. Durie,23 Jesus San Miguel,24
and Sagar Lonial,25 on behalf of the International Myeloma Working Group
1Sera`gnoli Institute of Hematology, Bologna University School of Medicine, Bologna, Italy; 2Department of Hematology, Mayo Clinic, Rochester, MN;
3Division of Hematology, University of Torino, Torino, Italy; 4Department of Hematology, University Hospital, Nantes, France; 5Department of
Lymphoma/Myeloma, M. D. Anderson Cancer Center, Houston, TX; 6Department of Hematology, Hospital Clinic, Barcelona, Spain; 7University Medical
Center, University of Hamburg, Hamburg, Germany; 8First Medical Department and Medical Oncology, Wilhelminenspital Hospital, Vienna, Austria;
9Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece; 10Service of Hematology, Hopital Purpan, Toulouse, France;
11Department of Hematology, Erasmus MC, Rotterdam, The Netherlands; 12Department of Medicine and Experimental Oncology, University of Torino, Torino,
Italy; 13 Division of Hematologic Malignancy, Dana-Farber Cancer Institute, Boston, MA; 14Fred Hutchinson Cancer Research Center, Seattle, WA;
15Department of Hematology, Medical Center, Aarhus University Hospital, Aarhus, Denmark; 16Department of Stem Cell Transplantation, University Hospital
Hamburg, Hamburg, Germany; 17Department of Medicine, Huddinge University Hospital, Stockholm, Sweden; 18Department of Hematology/Oncology, Mayo
Clinic Scottsdale, Scottsdale, AZ; 19John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ; 20Department of Hematology and
Oncology, Wuertzburg University Hospital, Wuertzburg, Germany; 21Mt Sinai Cancer Institute, New York, NY; 22Center for Lymphoma and Myeloma, Weill
Medical College of Cornell University, New York, NY; 23Hematologic Malignancies and Multiple Myeloma, Aptium Oncology, Los Angeles, CA; 24Hospital
Universitario de Salamanca, Centro de Investigacio´n del Ca´ncer, Instituto de Biologia Molecular y Celular del Ca´ncer (CIC IBMCC), Universidad de
Salamanca-Conscjo Superior de Investigaciones Cientificas (USAL-CSIC), Salamanca, Spain; and 25Department of Hematology and Medical Oncology,
Winship Cancer Institute, Emory University, Atlanta, GA
The role of high-dose therapy followed by
Up-front use of these induction treat-
ASCT has recently led to their use as
autologous stem cell transplantation
ments, in particular 3-drug combinations,
consolidation and maintenance therapies
(ASCT) in the treatment of multiple my-
has affected unprecedented rates of com-
after autotransplantation. Novel agents
eloma (MM) continues to evolve in the
plete response that rival those previously
and ASCT are complementary treatment
novel agent era. The choice of induction
seen with conventional chemotherapy and
strategies for MM. This article reviews the
therapy has moved from conventional
subsequent ASCT. Autotransplantation
current literature and provides important
chemotherapy to newer regimens incor-
applied after novel-agent-based induc-
perspectives and guidance on the major
porating the immunomodulatory deriva-
tion regimens provides further improve-
issues surrounding the optimal current
tives thalidomide or lenalidomide and the
ment in the depth of response, a gain that
management of younger, transplanta-
proteasome inhibitor bortezomib. These
translates into extended progression-free
tion-eligible MM patients. (Blood. 2011;
drugs combine well with traditional thera-
survival and, potentially, overall survival.
117(23):6063-6073)
pies and with one another to form various
High activity shown by immunomodula-
doublet, triplet, and quadruplet regimens.
tory derivatives and bortezomib before
Introduction
Multiple myeloma (MM) is a disease of the elderly. Overall, only
mide and lenalidomide have significantly contributed to major
35% of the patients are younger than 65 years at the time of
advances in MM therapy and prognosis.4,5
diagnosis, whereas the remaining two-thirds are older.1 Age is an
Thalidomide or bortezomib combined with melphalan and predni-
independent prognostic factor in MM2 and, importantly, provides a
sone represent new standards of care for elderly, transplantation-
major criterion by which patients can be considered eligible to
ineligible MM patients.6-8 In this setting, lenalidomide in combination
tolerate high-dose therapy (HDT) with autologous hematopoietic
with low-dose dexamethasone is an alternative treatment option.9 In
stem cell transplantation (ASCT). Over the last decade, the survival
younger patients, the novel agents have been incorporated into the
of patients with newly diagnosed MM, particularly those younger
therapeutic algorithm along with ASCT to improve clinical out-
than 60 years, has significantly improved.3 The widespread use of
comes.10-12 In particular, these drugs have been used as part of induction
ASCT and the introduction into clinical practice of the novel agents
therapy before ASCT and as consolidation/maintenance after autotrans-
bortezomib and the immunomodulatory derivatives (IMiDs) thalido-
plantation. This manuscript from the International Myeloma Working
Submitted January 26, 2011; accepted March 16, 2011. Prepublished online as
© 2011 by The American Society of Hematology
Blood First Edition paper, March 29, 2011; DOI 10.1182/blood-2011-02-297325.
The online version of this article contains a data supplement.
BLOOD, 9 JUNE 2011 VOLUME 117, NUMBER 23
6063

---

From bloodjournal.hematologylibrary.org by guest on January 31, 2012. For personal use only.
6064
CAVO et al
BLOOD, 9 JUNE 2011 VOLUME 117, NUMBER 23
Group (IMWG) presents an overview of the most recent studies of novel
after conventional induction chemotherapy was equivalent, early
agents combined with ASCT and focuses on the main areas of current
autotransplantation was associated with a longer event-free sur-
debate, including the choice of induction regimen, the role of post-
vival (EFS) and better quality of life.27 In the novel agent era, the
ASCT consolidation and maintenance therapies, the impact on
issue of early versus late ASCT needs to be reevaluated in the
prognosis of ASCT incorporating the new drugs, and the manage-
context of large randomized clinical trials. Two of these studies are
ment and prevention of major toxicities related to the use of novel
currently ongoing, one of them headed by the European Myeloma
therapies.
Network and the other performed by a consortium of centers in
France and the United States. While final results of these studies are
awaited, the IMWG recommends that ASCT should be offered at
What is younger?
some point in the course of the treatment program for a patient
eligible to receive HDT. Although favorable results with ASCT
There is no formal definition of a younger patient with MM,
up-front are backed by phase 3 studies, increasing numbers of
although this term is commonly used to identify a person for whom
patients and physicians, particularly in United States, are currently
ASCT is planned as part of the treatment program. As many phase
opting to collect stem cells early and deferring transplantation at
3 studies of ASCT have enrolled patients with an upper age limit
the time of relapse.
not exceeding 65 years,13-19 younger MM patients are often
operatively defined as being 65 years of age and younger. However,
this arbitrary cut-off does not exclude patients who are older than
Double ASCT
65 years from ASCT. In particular, in selected patients up to the age
of 70 to 75 years who are medically fit, ASCT is a treatment option
Five randomized trials directly addressed the question of single
that can be performed safely at most specialized transplantation or
versus double, or tandem, ASCT as up-front therapy for
myeloma centers.20 Unlike in younger patients, benefits from
MM.15,19,28-30 Results were conflicting because of differences
ASCT have not been consistently demonstrated in the elderly.
between studies with respect to their structural and methodologic
characteristics. In particular, although extended EFS with double
ASCT was observed in most of the trials, an OS benefit was
When to start myeloma-specific therapy
demonstrated in only 2 of them. A meta-analysis of data pooled
from controlled clinical trials (one of which has been recently
When symptomatic, or active, MM is diagnosed based on the
retracted) failed to show superior OS with double ASCT which, by
presence of organ damage related to the underlying malignant
the opposite, was associated with improved response rates and
clone (eg, hypercalcemia, renal insufficiency, anemia, and bone
EFS.31 A number of concerns related to the methodology of the
disease),21 therapy is required immediately. By contrast, patients
analysis and errors involving data extractions have been raised,
with asymptomatic or smoldering MM are closely observed
suggesting that these caveats might have negatively influenced the
without specific therapy until the disease progresses to a symptom-
conclusion.32,33 More recently, a report of long-term outcomes of
atic phase. Clinical trials are currently underway to investigate
several trials of autotransplantation(s) confirmed superior results
whether novel agents can delay the risk of progression from
offered by double ASCT compared with a single transplantation.34
smoldering to active MM and improve overall survival (OS).22 At
In 2 studies of double ASCT, post-hoc subgroup analyses
present, the IMWG does not recommend treatment for smoldering
showed that the second autotransplantation improved clinical
MM but considers patients at high risk of progression to symptom-
outcomes in those patients who failed high-quality responses after
atic disease as candidates for investigative clinical trials.
the first ASCT.15,19 However, a major limitation of these studies
was their lack of power to demonstrate the equivalence of 1 versus
2 transplants for patients with high-quality responses after the first
Single ASCT
course of HDT. With the recent availability of highly effective
novel agents, the role of single versus double ASCT is being
Over the last decade, ASCT has been considered the standard of
explored in the context of prospective, randomized clinical trials,
care for younger patients with newly diagnosed MM23-25 based on
such as that currently headed by the Bone Marrow Transplant
the increased rate of complete response (CR) and prolonged OS
Clinical Trials Network. In the meantime, the IMWG suggests
compared with conventional chemotherapy in several randomized
considering timely second ASCT in those patients who fail to
studies.13,14 However, not all the studies published so far have
achieve a very good partial response (VGPR) or better after the
uniformly demonstrated the superiority of ASCT over chemo-
first ASCT.
therapy at standard doses.16-18 A number of factors may account for
these discrepancies, including treatment crossover for patients
randomized to conventional treatment, possible bias in patient
Prognostic relevance of CR
selection criteria, and differences between studies with respect to
the intensity and duration of conventional therapy. A systematic
Attainment of CR after both induction therapy and ASCT is one of
review and meta-analysis of randomized studies has shown a
the strongest predictors of long-term outcomes35,36 and represents a
significant benefit with single ASCT in terms of prolonged
major endpoint of current treatment strategies incorporating auto-
progression-free survival (PFS), but not of OS.26 However, these
transplantation up-front. To more carefully identify high-quality
results should be cautiously interpreted because of methodologic
responses occurring beyond the CR level, the IMWG has recently
limitations of the analysis and significant heterogeneity across
introduced the category of stringent CR, as defined by negative
different studies. An alternative to autotransplantation up-front is to
immunofixation, normal free-light chain ratio, and absence of
delay HDT with ASCT at the time of relapse. Although in a pilot
clonal bone marrow plasma cells by immunohistochemistry.37 It is
study the length of OS for patients receiving early or late ASCT
probable that incorporation of novel agents into ASCT results in

---

From bloodjournal.hematologylibrary.org by guest on January 31, 2012. For personal use only.
BLOOD, 9 JUNE 2011 VOLUME 117, NUMBER 23
TREATMENT OF NEWLY DIAGNOSED MYELOMA
6065
Table 1. Phase 2 and 3 studies of thalidomide-dexamethasone and triplet thalidomide-based combinations in preparation for ASCT
After induction
After ASCT
Regimen
N
CR
PR, %
CR/ > VGPR, %
CR
PR, %
CR/ > VGPR, %
PFS
OS
Reference
TD vs
100
76
10/19
NR
NR
NR
NR
42
VAD (retrospective case-matched study)
100
52
8/14
NR
NR
NR
NR
TD vs
103
63
4/NR
NR
NR
NR
NR
44
VAD
104
41
0/NR
NR
NR
NR
NR
TD vs
100
66
NR/35
68
NR/44
NR
NR
43
Descamethasone
104
52
NR/13
62
NR/42
NR
NR
TAD vs
268
71
3/37
84
14/54
median, 34 mo
median, 73 mo
47
VAD
268
57
2/18
76
12/44
median, 22 mo
median, 60 mo
P
.001
P
.77
CTD vs
NR
87
19/NR
NR
51/NR
NR
NR
48
CVAD
NR
75
9/NR
NR
40/NR
NR
NR
TT2
THAL vs
323
NR
NR
NR
62/NR
5-yr, 56%
5-yr, 65%
46
TT2 without THAL
345
NR
NR
NR
43/NR
5-yr, 44%
5-yr, 65%
P
.01
P
.90
Double ASCT
THAL vs
135
NR
NR/30
NR
NR/68
4-yr, 51%
5-yr, 69%
45
Double ASCT without THAL (retrospective
135
NR
NR/15
NR
NR/49
4-yr, 31%
5-yr, 53%
case-matched study)
P
.001
P
.07
Studies incorporating thalidomide-dexamethasone throughout double ASCT are also included.
CTD indicates cyclophosphamide, thalidomide, dexamethasone; CVAD, cyclophosphamide added to VAD (vincristine, doxorubicin, dexamethasone); NR, not reported;
TAD, thalidomide, doxorubicin, dexamethasone; TD, thalidomide, dexamethasone; THAL, thalidomide; and TT2, Total Therapy 2.
increased rates of immunophenotypic and/or molecular remis-
in preparation for ASCT,42 a finding confirmed by a subsequent
sions38 compared with that reported in the recent past.
phase 3 study43 (Table 1). Based on the results of a randomized
Other studies have also emphasized the adverse prognostic
study showing a higher response rate with TD compared with
importance of residual focal lesions detected by magnetic reso-
high-dose dexamethasone44 (Table 1), the United States Food and
nance imaging.39 In contrast, sustained CR is predictive of favor-
Drug Administration granted accelerated approval for TD in
able long-term outcomes.40 Therefore, not only attainment of CR
patients with newly diagnosed MM. As a result, over the past years,
per se, but maintenance of a durable CR, appears to be a major
TD has emerged as one of the most commonly used induction
prognostic variable in MM. Interestingly, achievement of CR does
regimens in the United States and European countries (European
not seem to be of critical prognostic relevance for several
Union).
subgroups of patients, including those with low-risk disease or in
In 2 additional studies in which TD was incorporated into
whom active MM reverts to an indolent phase similar to that of
double ASCT and given from the outset through the second
monoclonal gammopathy of undetermined significance.41
ASCT45 or until relapse/progression,46 superior rates of CR or at
least VGPR, EFS, and OS were seen with TD plus double ASCT
compared with tandem transplantation not incorporating thalido-
Review of evidence supporting newer
mide (Table 1). However, the rate of adverse events, in particular
peripheral neuropathy and venous thromboembolism, was consis-
induction treatments in preparation for ASCT
tently high with thalidomide maintenance therapy and led to drug
discontinuation in 30% and 60% of patients after 2 and 4 years,
respectively.46
Patients who are eligible for early ASCT typically receive a limited
number of cycles of induction therapy to reduce tumor cell mass
and bone marrow plasma cell infiltration before collection of
peripheral blood stem cells. Compared with conventional treat-
Thalidomide-dexamethasone and a
ments used in the past, a number of novel agents are now available
cytotoxic drug
that affect increased rates of CR. Currently, these novel agents are
incorporated into induction regimens to enhance the depth of
Two phase 3 trials explored the activity of induction regimens
response before ASCT and further improve post-ASCT outcomes.
combining TD with doxorubicin or cyclophosphamide in transplan-
tation candidates. In one study, TD and doxorubicin provided a
significantly higher rate of VGPR or better compared with VAD
Thalidomide and dexamethasone
(37% vs 18%), a gain that was maintained after the first ASCT
(54% vs 44%, respectively).47 Median EFS for patients randomly
The activity of thalidomide, especially when combined with
assigned to TD and doxorubicin followed by post-ASCT thalido-
dexamethasone (TD), in the relapsed/refractory setting has pro-
mide maintenance was 34 months versus 22 months for those
vided the rationale for the design of phase 2 and 3 trials
assigned to VAD and subsequent maintenance with interferon.
investigating the role of this regimen in patients with newly
In another study, superior rates of CR both before and after
diagnosed disease.42-44 In 2005, a retrospective case-matched study
ASCT were seen with TD and cyclophosphamide compared with
provided the first demonstration of superior rate and depth of
cyclophosphamide added to VAD (pre-ASCT, 19% vs 9%; and
response affected by TD compared with VAD as induction therapy
post-ASCT, 51% vs 40%, respectively).48

---

From bloodjournal.hematologylibrary.org by guest on January 31, 2012. For personal use only.
6066
CAVO et al
BLOOD, 9 JUNE 2011 VOLUME 117, NUMBER 23
Table 2. Phase 2 studies of bortezomib-based regimens in preparation for ASCT
After induction
After transplantation
CR
PR,
CR
PR,
Regimen
N
%
CR/ > VGPR, %
%CR / > VGPR, %
PFS, median
OS, 30 mo
Reference
V (single agent)
64
41
NR (9)*/17
NR
NR
17 mo
30 mo, 79%
49
V
D
32
87.5
6 (25)*/NR
NR
NR
NR
NR
50
VD
48
66
NR (21)*/31
90
NR (33)*/55
NR
NR
51
V alternated with D
40
65
12.5/22.5
88
33/55
NR
NR
52
PAD-1
21
95
24 (5)*/62
95
43 (14)*/81
median, 29 mo
2-yr, 95%
54
PAD-2
20
89
11 (5)*/42
90
37 (5)*/53
median, 24 mo
2-yr, 73%
54
VDD
50
78
NR (27)*/NR
93
27/NR
NR
NR
56
VDD
40
85
NR (37.5)*/57.5
87
NR (57)*/77
2-yr, 80%
2-yr, 92%
57
CyBorD
33
88
3 (39)*/61
NR
NR (70)*/74
NR
NR
58
VCD
391
85.4
NR (15)*/37
NR
NR
NR
NR
59
VTD vs VTDC
49 vs 48
100 vs 96
(29)/69 vs (31)/69
100 vs 100
(50)/87 vs (44)/85
NR
1-yr, 94.1% vs 94.2%
66
TT3
VTD-PACE vs TT2
THAL
303 vs 323
NR vs NR
NR vs NR
NR vs NR
2-yr, 54/NR vs 51/NR
2-yr, 84% vs 77%
2-yr, 87% vs 83%
67
(retrospective comparison)
(P
.008)
(P
.12)
CyBorD indicates cyclophosphamide, bortezomib, dexamethasone; D, dexamethasone; NR, not reported; PACE, cisplatin, doxorubicin, cyclophosphamide, etoposide;
PAD, bortezomib, doxorubicin, dexamethasone; PAD-2, reduced-dose bortezomib; THAL, thalidomide; TT3, Total Therapy 3; V, bortezomib; VCD, bortezomib,
cyclophosphamide, dexamethasone; VDD, bortezomib, pegylated liposomal doxorubicin, dexamethasone; and VTD, bortezomib, thalidomide, dexamethasone.
*At least near CR.
PFS and OS compared with VAD induction and post-ASCT
Bortezomib and dexamethasone
thalidomide maintenance therapy (Table 2). Two additional phase
2 studies confirmed the activity of a PAD-like induction regimen
The role of up-front standard-dose bortezomib (1.3 mg/m2) given
incorporating pegylated liposomal doxorubicin (Table 2).56,57
twice weekly either as a single agent or with added dexamethasone
In addition, cyclophosphamide has also demonstrated substan-
in patients with suboptimal response to the first cycles of therapy
tial activity when combined with VD (CyBorD or VCD) in
was initially explored in patients who were either eligible or
preparation for ASCT.58,59 In 2 phase 2 studies, the rate of at least
ineligible for ASCT (Table 2).49,50 In 2 additional phase 2 studies,
VGPR was between 37% and 61%, a range that reflected heteroge-
bortezomib and high-dose dexamethasone (VD) were given either
neities between studies with respect to the number of planned
in combination51 or on an alternating basis52 before ASCT. The rate
treatment cycles and the delivered cyclophosphamide dose.
of at least VGPR was 31% with VD and 22.5% with the alternating
schedule; the corresponding value after ASCT was 55% in each of
the 2 studies. In a phase 3 study, VD was prospectively compared
Bortezomib, dexamethasone, and
with VAD as induction therapy in preparation for single or double
thalidomide
ASCT; in both arms, lenalidomide was given as post-ASCT
consolidation and maintenance therapy.53 After 4 21-day cycles, the
Preclinical data suggesting that IMiDs increase bortezomib activ-
rates of at least VGPR, including CR and near CR (nCR), affected
ity, provided the rationale for combining thalidomide with VD
by VD were significantly higher than with VAD (
VGPR, 38% vs
(VTD). Promising rates of high-quality responses reported with
15%; CR-nCR, 15% vs 6%, respectively), a gain maintained after
VTD in small cohorts of relapsed/refractory and newly diagnosed
both the first and second ASCT (
VGPR, 68% vs 47%; CR-nCR,
MM patients60 led to the design of a phase 3 study of VTD versus
39.5% vs 22.5%, respectively). A borderline, albeit not statistically
TD as induction therapy before, and consolidation therapy after,
significant, PFS benefit was seen in the VD arm compared with the
double ASCT.61 After three 21-day induction cycles, VTD was
VAD arm (median, 36 vs 30 months, respectively).
superior to TD with respect to all response categories, including
CR, CR-nCR (31% vs 11%), and at least VGPR (62% vs 28%).
Increased frequencies of high-quality responses in the VTD arm
Bortezomib-dexamethasone and a
compared with the TD arm were also seen after double autotrans-
cytotoxic drug
plantation and subsequent consolidation therapy (CR-nCR, 62% vs
45%;
VGPR, 85% vs 68%, respectively). The estimated 3-year
Cytotoxic drugs added to VD as part of a 3-drug regimen in
PFS for the VTD group of patients was significantly longer than for
preparation for ASCT have included doxorubicin or cyclophosph-
those assigned to TD plus double ASCT (68% vs 56%, respec-
amide (Table 2). A combination of bortezomib, doxorubicin, and
tively). In two additional phase 3 studies comparing VTD with
dexamethasone, referred to as PAD, was investigated in 2 small
either TD62 or VD63 as induction therapy in preparation for a single
cohorts of patients who received either standard-dose or reduced-
ASCT, superior rates of high-quality responses, both before and
dose bortezomib (1.0 mg/m2) on a twice-weekly basis (Table 2).54
after ASCT, and extended PFS62 were seen with the triplet regimen
In a phase 3 study, the PAD regimen was compared with VAD as
(Table 3). Remarkable activity of VTD was further confirmed by
induction therapy before 1 or 2 autotransplantations.55 Superior
several phase 2 studies,64,65 including a prospective comparison of
CR-nCR rates were seen with PAD compared with VAD after both
VTD with the same regimen combined with cyclophosphamide66
induction (11% vs 5%, respectively) and autotransplantation(s)
(Table 2).
(30% vs 15%). PAD induction followed by ASCT and subsequent
In Total Therapy 3, VTD combined with cisplatin, doxorubicin,
bortezomib maintenance was associated with significantly longer
cyclophosphamide, and etoposide was given as induction therapy

---

From bloodjournal.hematologylibrary.org by guest on January 31, 2012. For personal use only.
BLOOD, 9 JUNE 2011 VOLUME 117, NUMBER 23
TREATMENT OF NEWLY DIAGNOSED MYELOMA
6067
Table 3. Phase 3 trials of bortezomib-based regimens in preparation for ASCT
After induction
After ASCT
Regimen
N
CR
PR, %
CR/ > VGPR, %
CR
PR, %
CR/ > VGPR, %
PFS
OS
Reference
VD vs
223
78.5
6 (15)*/38
80
16 (35)*/54
median, 36 mo
3-yr, 81%
53
VAD
218
63
1 (6)*/15
77
9 (18)*/37
median, 30 mo
3-yr, 77%
(P
.06)
(P
.5)
VTD vs
236
93
19 (31)*/62
93
42 (55)*/82
3-yr, 68%
3-yr, 86%
61
TD
238
79
5 (11)*/28
84
30 (41)*/64
3-yr, 56%
3-yr, 84%
(P
.005)
(P
.3)
VBMCP/VBAD
V vs
129
75
21/36
73
38/51
38 mo
NR
62
VTD vs
130
85
35/60
77
46/65
27 mo
NR
TD
127
62
14/29
58
24/40
Not reached
NR
(P
.006)
PAD vs
371
78
NR (11)*/42
88
NR (30)*/61
3-yr, 36%
3-yr, 78%
55
VAD
373
55
NR (5)*/15
77
NR (15)*/36
3-yr, 27%
3-yr, 70%
(P
.01)
(P
.02)
VD vs
99
81
12 (22)*/35
84
33 (54)*/59
NR
NR
63
vTD
100
90
13 (32)*/51
90
30 (61)*/73
NR
NR
PAD indicates bortezomib, doxorubicin, dexamethasone; V, bortezomib; TD, thalidomide-dexamethasone; VAD, vincristine, doxorubicin, dexamethasone; VBAD,
vincristine, carmustine, doxorubicin, dexamethasone; VBMCP, vincristine, carmustine, melphalan, cyclophosphamide, prednisone; VD, bortezomib, dexamethasone; VTD,
bortezomib (1.3 mg/m2), thalidomide, dexamethasone; vTD, bortezomib (1.0 mg/m2), thalidomide, dexamethasone; and NR, not reported.
*At least near CR.
before, and consolidation after, double ASCT, whereas VTD
maintenance therapy was continued for 1 year after ASCT.67
Lenalidomide, dexamethasone, and
Compared with Total Therapy 2 incorporating TD into double
other agents
ASCT, Total Therapy 3 significantly improved 2-year EFS (77% vs
84%) and duration of CR.
Lenalidomide and dexamethasone were combined with bortezomib
to form a triplet regimen (RVD), which has been investigated in
limited series of patients with newly diagnosed MM.68-70 In a phase
Lenalidomide, dexamethasone, and other
1/2 study, a total of 66 patients who were either transplantation-
agents
eligible or ineligible for ASCT received a maximum of 8 RVD
cycles; in responders, RVD maintenance was allowed.69 After
Lenalidomide plus high-dose dexamethasone (480 mg total in a
4 cycles, the rate of at least nCR and VGPR was 6% and 11%,
28-day cycle; RD) was prospectively compared with lenalidomide
respectively. However, in approximately two-thirds of patients, the
and low-dose dexamethasone (160 mg total per cycle; Rd) as
quality of response improved from cycle 4 through cycle 8, and a
frontline therapy for MM.9 Patient enrollment into the study was
not restricted by age or eligibility for ASCT. Despite the overall
further improvement was also seen in the maintenance phase.
response rate, including VGPR or better within 4 cycles of therapy
In addition to RVD, alternative lenalidomide-containing
was significantly higher with RD compared with Rd (42% vs 24%,
regimens have included a combination of lenalidomide-
respectively), a substantially higher toxicity and early mortality
cyclophosphamide-dexamethasone and a quadruplet regimen in
was seen with RD, particularly in patients older than 65 years. On
which cyclophosphamide was added to RVD71 (Table 4). A
landmark analysis, the 3-year OS of patients who received ASCT
prospective comparison of RVD with VCD and cyclophosphamide
after RD or Rd was 92%; the corresponding value for patients who
combined with RVD given for up to 8 cycles has been recently
continued on primary therapy and did not receive ASCT was 79%.
reported; the rate of CR-nCR after 4 cycles was in the 7%, 3%, and
Table 4. Phase 2 and 3 trials of doublet and triplet lenalidomide-based induction treatments for transplant-eligible and transplant-ineligible
patients
After induction
After ASCT
CR
PR
CR/ > VGPR
Regimen
N
(best response), %
(best response), %
CR
PR, %
CR
nCR, %
PFS
OS
Reference
RD vs
223
81
5/50
NR
NR
median, 19 mo
median, not reached
9
Rd
222
70
4/40
NR
NR
median, 25 mo
median, not reached
(P
.02)
(P
.4)
RVD
66
100
29 (39)*/67
NR
NR
18 mo, 75%
18 mo, 97%
69
RVD vs
42
83
24 (40)*/50
NR
NR
NR
NR
72
VCD vs
32
75
22 (31)*/41
RVCD
42
86
24 (33)*/57
NR
NR
NR
NR
73
RVDD
57
4 cycles, 96
4 cycles, NR (30)*/58
NR
NR
NR
NR
CRD indicates cyclophosphamide, lenalidomide, dexamethasone; NR, not reported; RD, lenalidomide, high-dose dexamethasone; Rd, lenalidomide, low-dose
dexamethasone; RVD, lenalidomide, bortezomib, dexamethasone; RVCD, lenalidomide, bortezomib, cyclophosphamide, dexamethasone; RVDD, lenalidomide, bortezomib,
pegylated liposomal doxorubicin, dexamethasone; and VCD, bortezomib, cyclophosphamide, dexamethasone.
*At least near CR.

---

From bloodjournal.hematologylibrary.org by guest on January 31, 2012. For personal use only.
6068
CAVO et al
BLOOD, 9 JUNE 2011 VOLUME 117, NUMBER 23
10% range, respectively.72 An additional quadruplet regimen
Renal failure
incorporating lenalidomide, bortezomib, dexamethasone, and pegy-
In patients with MM and renal failure, rapid reduction of myeloma
lated liposomal doxorubicin was explored.73 After a median of
cell mass and recovery of normal renal function are critical goals of
4 cycles, the rates of CR-nCR and VGPR or better were 30% and
both myeloma-specific therapy and supportive care measures.85
58%, respectively.
Neither thalidomide86 nor bortezomib87 is excreted through the
kidneys, and dose adjustments are not required for patients with
renal impairment. In contrast, it is mandatory to modify the dose
and schedule of lenalidomide according to renal clearance.85 In
Special patient populations
general, bortezomib-based regimens are the preferred treatment
Cytogenetic abnormalities
option in this setting, as recently recommended by the IMWG.85
The prognostic value of major cytogenetic abnormalities and the
impact of novel agents on clinical outcomes of patients carrying
Major toxicities with IMiD- or
different cytogenetic changes have been recently reviewed by the
bortezomib-based induction therapies
IMWG.74 Detection at diagnosis of translocation t(4;14) and
t(14;16) or deletion of chromosome 17, del(17p), by fluorescence
Thalidomide and lenalidomide
in situ hybridization, as well as deletion/monosomy of del(13q) or
For patients who receive thalidomide up-front, either as a single
hypodiploidy by metaphase cytogenetics define approximately
agent or in combination therapy, the most common toxicities
one-fourth of patients75 who in the past years did not benefit from
include constipation, somnolence, and peripheral neuropathy (PN).88
ASCT and had shortened remission duration and OS.76,77
Thalidomide-induced PN is more frequently sensory or sensori-
Recent reports have suggested that incorporation of novel
motor, is dose-dependent (more prevalent with doses higher than
agents into ASCT may overcome, at least in part, the poor
200 mg/day) and duration-dependent (more likely to occur after
prognosis imparted by high-risk cytogenetic profiles. In two phase
6-12 months).89,90 Reduction of the dose or discontinuation of
3 studies of VD78 and PAD55 induction therapy followed by
thalidomide according to the severity of PN are measures com-
lenalidomide and bortezomib maintenance therapy, respectively,
monly used in clinical practice. Unlike thalidomide, lenalidomide
t(4;14)-positive patients had better outcomes than the control
induces myelosuppression, mainly neutropenia and thrombocytope-
groups who carried the same abnormality but received VAD
nia, which can be managed via dose reductions and/or hematopoi-
induction followed by maintenance therapy with either lenalido-
etic growth factor support.91 PN is uncommonly seen with lenalido-
mide78 or thalidomide.55 However, in both of these studies, t(4;14)
mide. Another major challenge to be considered in patients who
partly retained its adverse influence on PFS and OS, even among
receive thalidomide or lenalidomide up-front is the increased risk
patients treated with bortezomib-based induction regimens and
of thromboembolic complications.92,93 Adequate guidelines on the
subsequent maintenance with novel agents.55,78 In contrast, in a
most appropriate thromboprophylactic treatments have been pro-
phase 3 study of VTD induction and consolidation therapy plus
vided by the IMWG.92 Finally, hypothyroidism is an additional
double ASCT, PFS curves were almost identical regardless of the
important adverse event associated with long-term therapy incorpo-
presence or absence of t(4;14).61 In an additional study, incorpora-
rating thalidomide or lenalidomide. Long-term use of lenalidomide
tion of VTD into double ASCT as part of both induction and
is also associated with severe diarrhea and cramps in a subset
consolidation therapy and as post-ASCT maintenance therapy
of patients.
The effect of newer induction regimens, in particular those
resulted in improved CR duration, PFS, and OS for the gene
incorporating lenalidomide, on peripheral blood stem cell mobiliza-
expression profile-defined high-risk subgroup of patients carrying
tion and the optimal strategies to obtain adequate stem cell harvests
the MMSET/FGFR3 hybrid transcript.67 The role of bortezomib-
have recently been reviewed by the IMWG.94
based regimens and ASCT for the treatment of del(17p)-positive
patients needs to be carefully evaluated in larger sample sizes than those
Bortezomib
explored so far.78 In particular, areas of major interest include the
One of the most important nonhematologic toxicities of bortezomib
ability of less or more intense treatments (eg, doublet vs triplet or
is PN, which may lead to impaired quality of life. Bortezomib-
quadruplet combinations) given for different time periods (eg,
induced PN is predominantly sensory, although in
10% of cases
short-term vs long-term) to impact on the poor prognosis related to
motor neuropathy has been reported.95 Unlike neurologic toxicity
this high-risk cytogenetic profile.
associated with thalidomide, neuropathic pain, mainly located in
In most studies incorporating thalidomide as part of induction
the fingertips and toes, is a major problem with bortezomib. Major
therapy79 or as post-ASCT maintenance,80,81 the outcome of
risk factors of bortezomib-induced PN include the cumulative dose
patients with del(13q), t(4;14), and/or del(17p) was inferior to that
of the drug and treatment schedule. Attempts to decrease the rate
of patients who lacked these abnormalities. Conflicting results
and severity of neurologic toxicity in transplantation candidates
concerning the ability of lenalidomide to overcome the poor
have included either dose reduction of bortezomib given on a
prognosis associated with del(13q) and t(4;14) were found in
twice-weekly basis63 or once-weekly administration of the drug at a
2 retrospective studies of patients with relapsed/refractory MM.82,83
higher dose to maintain activity.96 In elderly, transplantation-
The adverse prognostic impact of del(17p) was emphasized in one
ineligible patients for whom treatment plan was composed of
of these studies.83 In a recent report on newly diagnosed MM
long-term exposure to melphalan and prednisone combined with
patients who were either transplantation-eligible or ineligible for
bortezomib (given twice weekly for 4 cycles, followed by once-
ASCT and received lenalidomide-dexamethasone up-front, both
weekly administration for the next 5 cycles), the overall risk of PN
response duration and PFS, but not OS, were significantly worse
was 47%, including 13% grade 3 or 4.8 In 2 recent studies of
when high-risk genetic abnormalities were present at baseline.84
melphalan and prednisone combined with standard-dose bor-

---

From bloodjournal.hematologylibrary.org by guest on January 31, 2012. For personal use only.
BLOOD, 9 JUNE 2011 VOLUME 117, NUMBER 23
TREATMENT OF NEWLY DIAGNOSED MYELOMA
6069
tezomib given on a weekly basis for 6 to 9 cycles, the incidence of
grade 3 or 4 PN was reduced to 6% to 7%, whereas efficacy was
Conclusions
retained.97,98 Whether these favorable results may be obtained in
In conclusion, incorporation of IMiDs and/or bortezomib into
transplantation-eligible patients who usually receive a shorter
newer regimens given in preparation for ASCT has been exten-
induction therapy is an issue not yet addressed in clinical trials.
sively explored using a wide range of different combinations.
Notably, compared with single-agent bortezomib short-term use of
Doublet therapies combining either an IMiD or bortezomib with
combined bortezomib and thalidomide was not associated with a
dexamethasone (eg, TD or Rd or VD) affected higher overall
major increase in the frequency of any grade and grade 3 or
response rates than traditional treatments,42,43,45,53 although the
4 PN.53,61,64,66 Besides symptomatic therapy, the optimal manage-
lowest rate of high-quality responses was seen with TD. Compared
ment of bortezomib-induced PN requires its early recognition and
with doublets, such as TD and VD, triplet induction regimens, in
dose reduction or discontinuation of the drug using a validated
particular, bortezomib plus thalidomide and dexamethasone (VTD),
algorithm; an alternative option may be to prolong the dosing
further increased the rate of CR and/or at least VGPR, both before
schedule. Provided these procedures are promptly adopted, approxi-
and after autotransplantation.61-63 In the context of triplet regimens
mately 70% of patients have partial or complete reversibility of
combining bortezomib with an IMiD, RVD is an attractive
their neurologic symptoms. The issue of the management of
alternative to VTD,70 although favorable results reported so far are
treatment-emergent PN in MM has been recently addressed.99
not backed by phase 3 clinical studies. Several newer induction
Severe thrombocytopenia occurs in approximately 5% or less of
treatments, such as VD, VTD, PAD, and Rd, have been included as
patients in the frontline setting. An additional adverse effect
a category 1 recommendation, which signifies a high-level of
commonly seen with bortezomib-based regimens is reactivation of
evidence and uniform consensus among panel members, in the
varicella zoster virus,100 a complication that can be virtually
United States National Comprehensive Cancer Network Clinical
abrogated with acyclovir prophylaxis.101
Practice Guidelines in Oncology for Multiple Myeloma Version
1.2011.23
Enhanced high-quality responses affected by newer induction
regimens translated into even higher frequencies of CR or at least
Role of novel agents as consolidation and
VGPR after single or double ASCT. Although extended PFS was
maintenance therapies after autologous
reported in several of these studies,45,46,47,53,55,61 no OS benefit was
generally seen, a finding that reflects the lack of adequate power
transplantation(s)
and/or follow-up to detect survival differences. Furthermore,
proving an OS benefit at this time is probably difficult because of
Consolidation treatment is generally short-term and aims to
the rapidly increasing availability of effective salvage therapies at
improve responses after ASCT. Upgraded rates of CR and
the time of relapse.
CR-nCR, in the range between 10% and 30%, have been recently
Based on these considerations and the close relationship
reported with post-ASCT use of bortezomib or lenalidomide as
between maximal response to induction therapy and favorable
single agents102,103 or with VTD.104 In several of these studies,
prognosis after ASCT, it is likely that many investigators in the
consolidation therapy with VTD yielded molecular remissions in
IMWG would recommend using one of the bortezomib-containing
up to 60% of patients.38,105
triplet regimens as up-front induction therapy in a transplantation-
Maintenance treatment is given for a prolonged time period
eligible MM patient. However, other IMWG investigators might
with the goal of extending the duration of response, PFS, and OS,
feel that until OS differences emerge, low-risk patients may have
while maintaining a good quality of life.106 Several randomized
the option of choosing either a doublet regimen with low morbidity,
studies showed a PFS benefit with thalidomide as single agent or
such as Rd, or a bortezomib-based triplet, provided that they are
combined with prednisone as maintenance therapy after
properly informed about the pros and cons, particularly the risk of
ASCT.46,47,80,81,107,108 In 2 of these studies, OS was extended in the
early PN with bortezomib. Besides once-weekly administration of
thalidomide arm,80,107 a gain lost when thalidomide was also given
bortezomib, the introduction into the clinical practice of subcutane-
as part of induction therapy before ASCT.46,47,81 Concerns exist
ous bortezomib that has recently shown a significantly lower risk of
about the use of thalidomide maintenance after ASCT, including
PN compared with intravenous bortezomib in patients with relapsed/
the possible emergence of tumor-resistant clones in patients with
refractory disease112 and carfilzomib, a second-generation irrevers-
prolonged exposure to this agents and its lack of efficacy in patients
ible proteasome inhibitor with significantly less neurotoxicity than
with adverse cytogenetic abnormalities.109 However, the major
bortezomib, may solve some of these issues in the near future.
caveat that precludes a widespread use of thalidomide maintenance
In the absence of randomized studies comparing different
is the toxicity related to long-term administration of this agent,
induction regimens, it is difficult to recommend one induction
primarily PN. In several studies, thalidomide-induced PN led to
regimen over another. However, particular patient and disease
discontinuation rates in the 60% range46,81 and impairment in
characteristics may guide the clinician to select the most appropri-
patients' quality of life.108 Lenalidomide is an attractive alternative
ate therapy. For instance, preliminary data suggest that bortezomib-
to thalidomide because of the lack of neurologic toxicity. Two
based regimens, such as VTD, VD, and PAD, can partially or
independent randomized trials have recently shown a significantly
completely abrogate the poor prognosis related to t(4;14),55,61,78
longer PFS110,111 for patients randomized to lenalidomide mainte-
although more mature data about del(17p) are needed. In patients
nance (5-15 mg/day) compared with the placebo group after a
presenting with acute renal failure, both bortezomib- and
single or double ASCT.105,106 An increased incidence of second
thalidomide-based regimens can be safely given, whereas lenalido-
primary malignancies, in the 7% range, has been recently reported.
mide requires appropriate dose reductions and frequent monitoring
Although a concerted effort is needed to better define the underly-
of blood counts. In patients at high risk of thromboembolic
ing mechanisms and identify risk factors, the optimal role and
complications, a bortezomib-based regimen may be preferable. In
duration of lenalidomide maintenance therapy need to be tested in
contrast, the presence of neuropathy at baseline might suggest
future clinical trials.
excluding bortezomib-based or thalidomide-based treatments in

---

From bloodjournal.hematologylibrary.org by guest on January 31, 2012. For personal use only.
6070
CAVO et al
BLOOD, 9 JUNE 2011 VOLUME 117, NUMBER 23
favor of a regimen, such as Rd. In the studies reported so far, the
supported by Janssen, Celgene, and Onyx (research support). R.N.
dose of dexamethasone was variable. However, high-dose dexameth-
was supported by Millenium and Celgene (research support).
asone is needed in those patients in whom a prompt reduction in
tumor cell mass is required. Finally, it is worth remembering that in
many countries novel-agent-based induction therapies for younger,
transplantation-eligible patients are not approved as yet. In these
Authorship
cases, the choice of induction regimen should be based on drug
availability; furthermore, referral of patients to a specialized
Contribution: All authors developed the consensus, provided
myeloma center with access to studies of novel agents is
critical review and edits to the manuscript, gave approval to the
recommended.
final manuscript, and significantly participated in the development
The usual choice of giving 3 to 6 cycles of induction therapy to
and writing of the manuscript.
maximize the depth of response before early ASCT represents a
Conflict-of-interest disclosure: M.C. received honoraria from
reasonable balance between maximum benefit and minimum
Janssen, Celgene, and Millennium. A.P. received honoraria from
toxicity. However, an alternative choice that can be discussed with
Celgene, Janssen, Merck, and Amgen and is on the advisory boards
the patient, particularly if response to therapy is favorable and
for Celgene and Janssen. P.M. received honoraria from Celgene
he/she is unwilling to proceed to early ASCT, is to continue
and Janssen. R.O. is on the advisory boards for Celgene, Millen-
induction for as long as maximal tumor reduction is achieved and
nium, Novartis, and Onyx. J.B. received honoraria for lectures
then to maintain response until relapse or progression, at which
from Janssen and Celgene. O.S. received honoraria from Amgen,
time salvage ASCT can be performed. In this scenario, especially in
Celgene, Janssen, and Novartis. H.L. received honoraria for
patients treated with lenalidomide-based regimens, peripheral
advisory boards for Celgene and is on the speaker's bureau of
blood stem cells should be collected early, after 4 to 6 cycles of
Celgene and Ortho-Biotech. M.A.D. received honoraria from
induction therapy. The best timing of ASCT in the novel agent era
Ortho-Biotech, Celgene, and Millenium. P.S. is on the advisory
represents an area of active debate and major interest. Unless final
boards for Janssen, Celgene, Millennium, and Onyx. M.B. received
results of ongoing clinical trials comparing early versus late ASCT
honoraria from Celgene and Janssen. K.C.A. is on the advisory
plus novel agents will be available, ASCT up-front should continue
boards for Celgene, Millennium, Onyx, Bristol-Myers Squibb,
to be considered the preferred approach for a patient who is eligible
Merck, and Novartis and is the founder of Acetylon. P.G.R. is on
to tolerate HDT. More recently, the treatment paradigm for
the advisory boards for Celgene, Millennium, Johnson & Johnson,
transplantation-eligible MM patients has continued to evolve with
Bristol-Myers Squibb, and Novartis. W.B. is a consultant and
the introduction of the novel agents as consolidation and mainte-
speaker for Millenium and Celgene, is a consultant for Onyx and
nance therapies. Mature results demonstrating the role, if any, of
Genzyme, and performed clinical trials for Millenium, Celgene,
consolidation therapy in improving clinical outcomes and the
Onyx, and Genzyme. H.E.J. is on the advisory board for and
impact of maintenance therapy on OS are needed before these
received honoraria from Janssen, Johnson & Johnson, and Amgen.
strategies are widely adopted. In the meantime, the choice of using
G.G. is a consultant for Fujomoto Pharmaceutical Cooperation
consolidation and/or maintenance therapy outside clinical trials is
Japan. P.L.B. is a consultant for Celgene and Novartis. D.H.V. is on
at the patient's and physician's discretion. If post-ASCT therapy
the advisory boards for Amgen, Celgene, and Onyx and on the
with lenalidomide is planned, the IMWG recommends that the
speaker's bureau of Millennium and Celgene. R.N. is a consultant
benefits of extended disease control versus potential risks of second
and speaker for Millenium and Celgene, received research support
malignancies with continued lenalidomide therapy be discussed
from Millenium and Celgene, and is a consultant for Onyx.
with each patient. For many other important and still unaddressed
B.G.M.D. is on the advisory boards for Millennium, Celgene, and
questions, prospective randomized phase 3 studies are currently
Onyx. J.F.S.-M. is on advisory boards for Millenium, Celgene, and
planned or underway.
Janssen-Cilag. S.L. is a consultant for Millennium, Celgene,
Bristol-Myers Squibb, Novartis, Merck, and Onyx. The remaining
authors declare no competing financial interests.
Acknowledgments
Correspondence: Michele Cavo, Istituto di Ematologia Sera`gnoli,
Azienda Ospedaliero-Universitaria, Policlinico S. Orsola-Mal-
R.O. was supported by Celgene and Millennium (research fund-
pighi, via Massarenti 9, 40138, Bologna, Italy; e-mail:
ing). J.B. was supported by Jansen and Celgene. O.S. was
michele.cavo@unibo.it; and S. Vincent Rajkumar, Mayo Clinic,
supported by Janssen and Novartis (research funding). P.S. was
200 First St SW, Rochester, MN 55905; e-mail: rajks@mayo.edu.
References
1. Altekruse SF, Kosary C, Krapcho M, Neyman N,
4. Cavo M, Baccarani M. The changing landscape
autologous stem cell transplantation in elderly
Aminou R, Waldron W. SEER Cancer Statistics
of myeloma therapy. N Engl J Med. 2006;
patients with multiple myeloma (IFM 99-06): a
Review, 1975-2007, National Cancer Institute,
354(10):1076-1078.
randomised trial. Lancet. 2007;370(9594):1209-
Bethesda, MD. http://www.seercancergov/csr/
5. Kumar SK, Rajkumar SV, Dispenzieri A, et al.
1218.
1975_2007. Accessed March 10, 2011.
Improved survival in multiple myeloma and the
8. San Miguel JF, Schlag R, Khuageva NK, et al.
2. Ludwig H, Durie BG, Bolejack V, et al. Myeloma
impact of novel therapies. Blood. 2008;111(5):
Bortezomib plus melphalan and prednisone for
in patients younger than age 50 years presents
2516-2520.
initial treatment of multiple myeloma. N Engl
with more favorable features and shows better
6. Palumbo A, Bringhen S, Liberati AM, et al. Oral
J Med. 2008;359(9):906-917.
survival: an analysis of 10 549 patients from the
melphalan, prednisone, and thalidomide in
International Myeloma Working Group. Blood.
9. Rajkumar SV, Jacobus S, Callander NS, et al.
elderly patients with multiple myeloma: updated
2008;111(8):4039-4047.
Lenalidomide plus high-dose dexamethasone
results of a randomized, controlled trial. Blood.
versus lenalidomide plus low-dose dexametha-
3. Brenner H, Gondos A, Pulte D. Recent major im-
2008;112(8):3107-3114.
sone as initial therapy for newly diagnosed mul-
provement in long-term survival of younger pa-
7. Facon T, Mary JY, Hulin C, et al. Melphalan and
tiple myeloma: an open-label randomised con-
tients with multiple myeloma. Blood. 2008;111(5):
prednisone plus thalidomide versus melphalan
trolled trial. Lancet Oncol. 2010;11(1):29-37.
2521-2526.
and prednisone alone or reduced-intensity

---

From bloodjournal.hematologylibrary.org by guest on January 31, 2012. For personal use only.
BLOOD, 9 JUNE 2011 VOLUME 117, NUMBER 23
TREATMENT OF NEWLY DIAGNOSED MYELOMA
6071
10. Bensinger W. Stem-cell transplantation for mul-
tion versus chemotherapy for newly diagnosed
thalidomide and dexamethasone over vincristine-
tiple myeloma in the era of novel drugs. J Clin
multiple myeloma: a systematic review and meta-
doxorubicin dexamethasone (VAD) as primary
Oncol. 2008;26(3):480-492.
analysis of randomized controlled trials. Biol
therapy in preparation for autologous transplanta-
11. Lonial S, Cavenagh J. Emerging combination
Blood Marrow Transplant. 2007;13(2):183-196.
tion for multiple myeloma. Blood. 2005;106(1):35-
treatment strategies containing novel agents in
27. Fermand JP, Ravaud P, Chevret S, et al. High-
39.
newly diagnosed multiple myeloma. Br J Haema-
dose therapy and autologous peripheral blood
43. Macro M, Divine M, Uzunhan Y, et al. Dexameth-
tol. 2009;145(6):681-708.
stem cell transplantation in multiple myeloma:
asone
thalidomide (Dex/Thal) compared to
12. Stewart AK, Richardson PG, San-Miguel JF.
up-front or rescue treatment? Results of a multi-
VAD as a pre-transplant treatment in newly diag-
How I treat multiple myeloma in younger patients.
center sequential randomized clinical trial. Blood.
nosed multiple myeloma (MM): a randomized trial
Blood. 2009;114(27):5436-5443.
1998;92(9):3131-3136.
[abstract]. Blood. 2006;108(11):Abstract 57.
13. Attal M, Harousseau JL, Stoppa AM, et al. A pro-
28. Segeren CM, Sonneveld P, van der Holt B, et al.
44. Rajkumar SV, Blood E, Vesole D, Fonseca R,
spective, randomized trial of autologous bone
Overall and event-free survival are not improved
Greipp PR. Phase III clinical trial of thalidomide
marrow transplantation and chemotherapy in
by the use of myeloablative therapy following in-
plus dexamethasone compared with dexametha-
multiple myeloma: Intergroupe Francais du My-
tensified chemotherapy in previously untreated
sone alone in newly diagnosed multiple myeloma:
elome. N Engl J Med. 1996;335(2):91-97.
patients with multiple myeloma: a prospective
a clinical trial coordinated by the Eastern Cooper-
randomized phase 3 study. Blood. 2003;101(6):
ative Oncology Group. J Clin Oncol. 2006;24(3):
14. Child JA, Morgan GJ, Davies FE, et al. High-dose
2144-2151.
431-436.
chemotherapy with hematopoietic stem-cell res-
45. Cavo M, Di Raimondo F, Zamagni E, et al. Short-
cue for multiple myeloma. N Engl J Med. 2003;
29. Fermand J. High dose therapy supported with
term thalidomide incorporated into double autolo-
348(19):1875-1883.
autologous blood stem cell transplantation in mul-
tiple myeloma: long term follow-up of the pro-
gous stem-cell transplantation improves out-
15. Attal M, Harousseau JL, Facon T, et al. Single
spective studies of the MAG group [abstract].
comes compared with double autotransplantation
versus double autologous stem-cell transplanta-
Haematologica. 2005;90(suppl 1):Abstract 40.
for multiple myeloma. J Clin Oncol. 2009;27(30):
tion for multiple myeloma. N Engl J Med. 2003;
5001-5007.
349(26):2495-2502.
30. Goldschmidt H. Single vs. double high-dose
therapy in multiple myeloma: second analysis of
46. Barlogie B, Tricot G, Anaissie E, et al. Thalido-
16. Blade J, Rosinol L, Sureda A, et al. High-dose
the GMMG-HD2 trial [abstract]. Haematologica.
mide and hematopoietic-cell transplantation for
therapy intensification compared with continued
2005;90(suppl 1):Abstract 38.
multiple myeloma. N Engl J Med. 2006;354(10):
standard chemotherapy in multiple myeloma pa-
1021-1030.
tients responding to the initial chemotherapy:
31. Kumar A, Kharfan-Dabaja MA, Glasmacher A,
47. Lokhorst HM, van der Holt B, Zweegman S, et al.
long-term results from a prospective randomized
Djulbegovic B. Tandem versus single autologous
A randomized phase 3 study on the effect of tha-
trial from the Spanish cooperative group
hematopoietic cell transplantation for the treat-
lidomide combined with adriamycin, dexametha-
PETHEMA. Blood. 2005;106(12):3755-3759.
ment of multiple myeloma: a systematic review
and meta-analysis. J Natl Cancer Inst. 2009;
sone, and high-dose melphalan, followed by tha-
17. Fermand JP, Katsahian S, Divine M, et al. High-
101(2):100-106.
lidomide maintenance in patients with multiple
dose therapy and autologous blood stem-cell
myeloma. Blood. 2010;115(6):1113-1120.
transplantation compared with conventional treat-
32. Giralt S, Vesole DH, Somlo G, et al. Re: Tandem
48. Owen RG, Jackson GH, et al. MRC Myeloma IX:
ment in myeloma patients aged 55 to 65 years:
vs single autologous hematopoietic cell trans-
preliminary results from the intensive pathway
long-term results of a randomized control trial
plantation for the treatment of multiple myeloma:
study [abstract]. Clin Lymphoma Myeloma. 2009;
from the Group Myelome-Autogreffe. J Clin On-
a systematic review and meta-analysis. J Natl
9(1):Abstract 546.
col. 2005;23(36):9227-9233.
Cancer Inst. 2009;101(13):964; author reply 6-7.
49. Richardson PG, Xie W, et al. Single-agent bor-
18. Barlogie B, Kyle RA, Anderson KC, et al. Stan-
33. Mehta J. Re: Tandem vs single autologous hema-
tezomib in previously untreated multiple my-
dard chemotherapy compared with high-dose
topoietic cell transplantation for the treatment of
eloma: efficacy, characterization of peripheral
chemoradiotherapy for multiple myeloma: final
multiple myeloma: a systematic review and meta-
neuropathy, and molecular correlations with re-
results of phase III US Intergroup Trial S9321.
analysis. J Natl Cancer Inst. 2009;101(20):1430-
sponse and neuropathy. J Clin Oncol. 2009;
J Clin Oncol. 2006;24(6):929-936.
1431; author reply 1-3.
27(21):3518-3525.
19. Cavo M, Tosi P, Zamagni E, et al. Prospective,
34. Barlogie B, Attal M, Crowley J, et al. Long-term
50. Jagannath S, Durie BG, Wolf J, et al. Bortezomib
randomized study of single compared with double
follow-up of autotransplantation trials for multiple
therapy alone and in combination with dexameth-
autologous stem-cell transplantation for multiple
myeloma: update of protocols conducted by the
asone for previously untreated symptomatic mul-
myeloma: Bologna 96 clinical study. J Clin Oncol.
Intergroupe Francophone du Myelome, South-
tiple myeloma. Br J Haematol. 2005;129(6):776-
2007;25(17):2434-2441.
west Oncology Group, and the University of Ar-
kansas for Medical Sciences. J Clin Oncol. 2010;
783.
20. Kumar SK, Dingli D, Lacy MQ, et al. Autologous
28(7):1209-1214.
51. Harousseau JL, Attal M, Leleu X, et al. Bor-
stem cell transplantation in patients of 70 years
tezomib plus dexamethasone as induction treat-
and older with multiple myeloma: results from a
35. Harousseau JL, Attal M, Avet-Loiseau H. The role
ment prior to autologous stem cell transplantation
matched pair analysis. Am J Hematol. 2008;
of complete response in multiple myeloma.
in patients with newly diagnosed multiple my-
83(8):614-617.
Blood. 2009;114(15):3139-3146.
eloma: results of an IFM phase II study. Haema-
21. International Myeloma Working Group. Criteria
36. Chanan-Khan Giralt S. Importance of achieving a
tologica. 2006;91(11):1498-1505.
for the classification of monoclonal gammopa-
complete response in multiple myeloma, and the
52. Rosinol L, Oriol A, Mateos MV, et al. Phase II
thies, multiple myeloma and related disorders: a
impact of novel agents. J Clin Oncol. 2010;
PETHEMA trial of alternating bortezomib and
report of the International Myeloma Working
28(15):2612-2624.
dexamethasone as induction regimen before
Group. Br J Haematol. 2003;121(5):749-757.
37. Durie BG, Harousseau JL, Miguel JS, et al. Inter-
autologous stem-cell transplantation in younger
22. Mateos MV, Herna´ndez T, de la Rubia J, et al.
national uniform response criteria for multiple my-
patients with multiple myeloma: efficacy and clini-
Multicenter, randomized, open-label, phase III
eloma. Leukemia. 2006;20(9):1467-1473.
cal implications of tumor response kinetics. J Clin
trial of lenalidomide-dexamethasone vs therapeu-
38. Ladetto M, Pagliano G, Ferrero S, et al. Major
Oncol. 2007;25(28):4452-4458.
tic abstention in smoldering multiple myeloma at
tumor shrinking and persistent molecular remis-
53. Harousseau J-L, Attal M, Avet-Loiseau H, et al.
high risk of progression to symptomatic MM: re-
sions after consolidation with bortezomib, thalido-
Bortezomib plus dexamethasone is superior to
sults of the first interim analysis [abstract]. Blood.
mide, and dexamethasone in patients with au-
vincristine plus doxorubicin plus dexamethasone
2009;114(22):Abstract 614.
tografted myeloma. J Clin Oncol. 2010;28(12):
as induction treatment prior to autologous stem-
23. National Cancer Comprehensive Network. NCCN
2077-2084.
cell transplantation in newly diagnosed multiple
Clinical practice guidelines in oncology: multiple
39. Walker R, Barlogie B, Haessler J, et al. Magnetic
myeloma: results of the IFM 2005-01 phase III
myeloma. http://wwwnccnorg/professionals/phy-
resonance imaging in multiple myeloma: diagnos-
trial. J Clin Oncol. 2010;28(30):4621-4629.
sician_gls/PDF/myelomapdf. Accessed March
tic and clinical implications. J Clin Oncol. 2007;
54. Popat R, Oakervee HE, Hallam S, et al. Bor-
10, 2011.
25(9):1121-1128.
tezomib, doxorubicin and dexamethasone (PAD)
24. Barosi G, Boccadoro M, Cavo M, et al. Manage-
40. Barlogie B, Anaissie E, Haessler J, van Rhee F,
front-line treatment of multiple myeloma: updated
ment of multiple myeloma and related-disorders:
et al. Complete remission sustained 3 years from
results after long-term follow-up. Br J Haematol.
guidelines from the Italian Society of Hematology
treatment initiation is a powerful surrogate for ex-
2008;141(4):512-516.
(SIE), Italian Society of Experimental Hematology
tended survival in multiple myeloma. Cancer.
55. Sonneveld P, Schmidt-Wolf IGH, Van der Holt B,
(SIES) and Italian Group for Bone Marrow Trans-
2008;113(2):355-359.
et al. HOVON-65/GMMG-HD4 randomized phase
plantation (GITMO). Haematologica. 2004;89(6):
41. Pineda-Roman M, Bolejack V, Arzoumanian V,
III trial comparing bortezomib, doxorubicin, dexa-
717-741.
et al. Complete response in myeloma extends
methasone (PAD) vs VAD followed by high-dose
25. Smith A, Wisloff F, Samson D. Guidelines on the
survival without, but not with history of prior
melphalan and maintenance with bortezomib or
diagnosis and management of multiple myeloma
monoclonal gammopathy of undetermined signifi-
thalidomide in patients with newly diagnosed mul-
2005. Br J Haematol. 2006;132(4):410-451.
cance or smouldering disease. Br J Haematol.
tiple myeloma [abstract]. Blood. 2010;116(21):
26. Koreth J, Cutler CS, Djulbegovic B, et al. High-
2007;136(3):393-399.
Abstract 40.
dose therapy with single autologous transplanta-
42. Cavo M, Zamagni E, Tosi P, et al. Superiority of
56. Belch A, Reece DE, Bahlis NJ, et al. Bortezomib

---

From bloodjournal.hematologylibrary.org by guest on January 31, 2012. For personal use only.
6072
CAVO et al
BLOOD, 9 JUNE 2011 VOLUME 117, NUMBER 23
[VELCADE], pegylated liposomal doxorubicin
Frontline therapy with bortezomib, lenalidomide
85. Dimopoulos MA, Terpos E, Chanan-Khan A, et al.
[DOXIL/CAELYX] and dexamethasone in the
and dexamethasone (VRD) followed by autolo-
Renal impairment in patients with multiple my-
treatment of previously untreated multiple
gous stem cell transplantation, VRD consolida-
eloma: a consensus statement on behalf of the
myeloma patients: impact on quality-of-life
tion and lenalidomide maintenance in newly diag-
International Myeloma Working Group. J Clin On-
[abstract]. Blood. 2007;110(11):Abstract 1058.
nosed multiple myeloma patients: primary results
col. 2010;28(33):4976-4984.
57. Jakubowiak AJ, Kendall T, Al-Zoubi A, et al.
of the IFM 2008 phase II study [abstract]. Blood.
86. Tosi P, Zamagni E, Tacchetti P, et al. Thalidomide-
Phase II trial of combination therapy with bor-
2010;116(21):Abstract 624.
dexamethasone as induction therapy prior to au-
tezomib, pegylated liposomal doxorubicin, and
71. Kumar S, Flinn I, Noga SJ, et al. Bortezomib,
tologous stem-cell transplantation in patients with
dexamethasone in patients with newly diagnosed
dexamethasone, cyclophosphamide and lena-
newly diagnosed multiple myeloma and renal in-
myeloma. J Clin Oncol. 2009;27(30):5015-5022.
lidomide combination for newly diagnosed mul-
sufficiency. Biol Blood Marrow Transplant. 2010;
58. Reeder CB, Reece DE, Kukreti V, et al. Cyclo-
tiple myeloma: phase I results from the multi-
16(8):1115-1121.
phosphamide, bortezomib and dexamethasone
center EVOLUTION study. Leukemia. 2010;
87. San-Miguel JF, Richardson PG, Sonneveld P, et
induction for newly diagnosed multiple myeloma:
24(7):1350-1356.
al. Efficacy and safety of bortezomib in patients
high response rates in a phase II clinical trial.
72. Kumar S, Flinn IW, Richardson PG, et al. Novel
with renal impairment: results from the APEX
Leukemia. 2009;23(7):1337-1341.
three- and four-drug combination regimens of
phase 3 study. Leukemia. 2008;22(4):842-849.
59. Einsele H, Liebisch P, Langer C, et al. Velcade,
bortezomib, dexamethasone, cyclophosphamide,
88. Ghobrial IM, Rajkumar SV. Management of tha-
intravenous cyclophosphamide and dexametha-
and lenalidomide, for previously untreated mul-
lidomide toxicity. J Support Oncol. 2003;1(3):194-
sone (VCD) induction for previously untreated
tiple myeloma: results from the multicenter, ran-
205.
multiple myeloma (German DSMM XIa Trial)
domized, phase 2 EVOLUTION study [abstract].
89. Plasmati R, Pastorelli F, Cavo M, et al. Neuropa-
[abstract]. Blood. 2009;114(22):Abstract 131.
Blood. 2010;116(21):Abstract 621.
thy in multiple myeloma treated with thalidomide:
60. Wang M, Giralt S, Delasalle K, Handy B,
73. Jakuboviak AJ, Reece DE, Craig C, et al. Lena-
a prospective study. Neurology. 2007;69(6):573-
Alexanian R. Bortezomib in combination with tha-
lidomide, bortezomib, pegylated liposomal doxo-
581.
lidomide-dexamethasone for previously untreated
rubicin and dexamethasone in newly diagnosed
90. Tosi P, Zamagni E, Cellini C, et al. Neurological
multiple myeloma. Hematology. 2007;12(3):235-
multiple myeloma: updated results of a phase I/II
toxicity of long-term ( 1 yr) thalidomide therapy
239.
MMRC trial [abstract]. Blood. 2009;114(22):Ab-
in patients with multiple myeloma. Eur J Haema-
stract 132.
61. Cavo M, Tacchetti P, Patriarca F, et al. Bor-
tol. 2005;74(3):212-216.
tezomib, thalidomide and dexamethasone com-
74. Fonseca R, Bergsagel PL, Drach J, et al. Interna-
91. Mateos M-V. Management of treatment-related
pared with thalidomide and dexamethasone as
tional Myeloma Working Group molecular classifi-
adverse events in patients with multiple myeloma.
induction before and consolidation therapy after
cation of multiple myeloma: spotlight review. Leu-
Cancer Treat Rev. 2010;36(suppl 2):524-532.
double autologous stem cell transplantation in
kemia. 2009;23(12):2210-2221.
92. Palumbo A, Rajkumar SV, Dimopoulos MA, et al.
newly diagnosed multiple myeloma: results from
75. Stewart AK, Bergsagel PL, Greipp PR, et al. A
Prevention of thalidomide- and lenalidomide-
a randomized phase III study. Lancet. 2010;
practical guide to defining high-risk myeloma for
associated thrombosis in myeloma. Leukemia.
379(9758):2075-2085.
clinical trials, patient counseling and choice of
2008;22(2):414-423.
62. Rosin~ol L, Cibeira MT, Mateos MV, et al. A phase
therapy. Leukemia. 2007;21(3):529-534.
III PETHEMA/GEM study of induction therapy
93. Zamagni E, Brioli A, Tacchetti P, Zannetti B,
76. Gertz MA, Lacy MQ, Dispenzieri A, et al. Clinical
prior autologous stem cell transplantation in mul-
Pantani L, Cavo M. Multiple myeloma, venous
implications of t(11;14) (q13;q32), t(4;14) (p16.3;
tiple myeloma: superiority of VTD (bortezomib/
thromboembolism and treatment related risk of
q32) and
17p13 in myeloma patients treated
thalidomide/dexamethasone) over TD and VB-
thrombosis. Semin Thromb Hemost. 2011;37(3):
with high-dose therapy. Blood. 2005;106(8):2837-
MCP/VBAD plus bortezomib [abstract]. Blood.
209-219.
2840.
2010;116(21):Abstract 307.
77. Cavo M, Terragna C, Renzulli M, et al. Poor out-
94. Kumar S, Giralt S, Stadtmauer EA, et al. Mobili-
63. Harousseau J-L, Avet Loiseau H, Facon T, et al.
come with front-line autologous transplantation in
zation in myeloma revisited: IMWG consensus
Bortezomib plus dexamethasone (VD) versus
t(4;14) multiple myeloma: low complete remission
perspectives on stem cell collection following ini-
reduced-dose bortezomib plus thalidomide plus
rate and short duration of remission. J Clin Oncol.
tial therapy with thalidomide-, lenalidomide-, or
dexamethasone (vTD) as induction treatment
2006;24(3):e4-e5.
bortezomib-containing regimens. Blood. 2009;
prior to autologous stem-cell transplantation
114(9):1729-1735.
78. Avet Loiseau H, Leleu X, Roussel M, et al. Bor-
(ASCT) in newly diagnosed multiple myeloma
tezomib plus dexamethasone induction improves
95. Argyriou AA, Iconomou G, Kalofonos HP.
(MM) [abstract]. Blood. 2009;114(22):Abstract
outcome of patients with t(4;14) but not outcome
Bortezomib-induced peripheral neuropathy in
354.
of patients with del(17p). J Clin Oncol. 2010;
multiple myeloma: a comprehensive review of the
64. Kaufman JL, Nooka A, Vrana M, et al. Bor-
28(30):4630-4634.
literature. Blood. 2008;112(5):1593-1599.
tezomib, thalidomide, and dexamethasone as
79. Zamagni E, Testoni N, Terragna C, et al. Prognos-
96. Reeder CB, Reece DE, Kukreti V, et al. Once-
induction therapy for patients with symptomatic
tic impact of cytogenetic abnormalities on out-
versus twice-weekly bortezomib induction
multiple myeloma. Cancer. 2010;116(13):3143-
comes of newly diagnosed multiple myeloma pa-
therapy with CyBorD in newly diagnosed multiple
3151.
tients treated with thalidomide-dexamethasone
myeloma. Blood. 2010;115(16):3416-3417.
65. Bensinger W, Jagannath S, Vescio R, et al.
incorporated into double autologous stem-cell
97. Bringhen S, Larocca A, Rossi D, et al. Efficacy
Phase 2 study of two sequential three-drug com-
transplantation: an analysis of 593 patients [ab-
and safety of once-weekly bortezomib in multiple
binations containing bortezomib, cyclophosph-
stract]. Blood. 2010;116(21):Abstract 3562.
myeloma patients. Blood. 2010;116(23):4745-
amide and dexamethasone, followed by bort-
80. Attal M, Harousseau JL, Leyvraz S, et al. Mainte-
4753.
ezomib, thalidomide and dexamethasone as
nance therapy with thalidomide improves survival
98. Mateos MV, Oriol A, Martinez-Lopez J, et al.
frontline therapy for multiple myeloma.
in patients with multiple myeloma. Blood. 2006;
Bortezomib, melphalan, and prednisone versus
Br J Haematol. 2010;148(4):562-568.
108(10):3289-3294.
bortezomib, thalidomide, and prednisone as
66. Ludwig H, Greil R, Masszi T, et al. Bortezomib,
81. Morgan GJ, Davies FE, Gregory WM, et al. Tha-
induction therapy followed by maintenance treat-
thalidomide, and dexamethasone (VTD) versus
lidomide maintenance significantly improves pro-
ment with bortezomib and thalidomide versus
VTD plus cyclophosphamide as induction therapy
gression-free survival (PFS) and overall survival
bortezomib and prednisone in elderly patients
in previously untreated multiple myeloma patients
(OS) of myeloma patients when effective relapse
with untreated multiple myeloma: a randomized
eligible for HDT-ASCT: a randomized phase
treatments are used: MRC Myeloma IX results
trial. Lancet Oncol. 2010;11(10):934-941.
2 trial [abstract]. Blood. 2009;114(22):Abstract
[abstract]. Blood. 2010;116(21):Abstract 623.
99. Delforge M, Blade´ J, Dinopoulos MA, et al. Treat-
2312.
82. Avet Loiseau H, Soulier J, Fermand JP, et al. Im-
ment-related peripheral neuropathy in multiple
67. Pineda-Roman M, Zangari M, Haessler J, et al.
pact of high-risk cytogenetics and prior therapy
myeloma: the challenge continues. Lancet Oncol.
Sustained complete remissions in multiple
on outcomes in patients with advanced relapsed
2010;11(11):1086-1095.
myeloma linked to bortezomib in total therapy
or refractory multiple myeloma treated with lena-
100. Chanan-Khan A, Sonneveld P, Schuster MW, et
3: comparison with total therapy 2. Br J Haema-
lidomide plus dexamethasone. Leukemia. 2010;
al. Analysis of herpes zoster events among
tol. 2008;140(6):625-634.
24(3):623-628.
bortezomib-treated patients in the phase III APEX
68. Wang M, Delasalle K, Giralt S, Alexanian R.
83. Reece D, Song KW, Fu T, et al. Influence of cyto-
study. J Clin Oncol. 2008;26(29):4784-4790.
Rapid control of previously untreated multiple
genetics in patients with relapsed or refractory
101. Vickrey E, Allen S, Mehta J, Singhal S. Acyclovir
myeloma with bortezomib-lenalidomide-
multiple myeloma treated with lenalidomide plus
to prevent reactivation of varicella zoster virus
dexamethasone (BLD). Hematology. 2010;15(2):
dexamethasone: adverse effect of deletion
(herpes zoster) in multiple myeloma patients re-
70-73.
17p13. Blood. 2009;114(3):522-525.
ceiving bortezomib therapy. Cancer. 2009;115(1):
69. Richardson PG, Weller E, Lonial S, et al. Lena-
84. Kapoor P, Kumar S, Fonseca R, et al. Impact of
229-232.
lidomide, bortezomib, and dexamethasone com-
risk stratification on outcome among patients with
102. Mellqvist U-H, Westin J, Gimsing P, et al. Im-
bination therapy in patients with newly diagnosed
multiple myeloma receiving initial therapy with
proved response rate with bortezomib consolida-
multiple myeloma. Blood. 2010;116(5):679-686.
lenalidomide and dexamethasone. Blood. 2009;
tion after high dose melphalan: first results of a
70. Roussel M, Avet-Loiseau H, Moreau P, et al.
114(3):518-521.
Nordic Myeloma Study Group randomized phase

---

From bloodjournal.hematologylibrary.org by guest on January 31, 2012. For personal use only.
BLOOD, 9 JUNE 2011 VOLUME 117, NUMBER 23
TREATMENT OF NEWLY DIAGNOSED MYELOMA
6073
III trial [abstract]. Blood. 2009;114(22):Abstract
dexamethasone as consolidation therapy after
109. Cavo M, Pantani L, Tacchetti P, et al. Thalidomide
530.
double autologous transplantation for multiple
maintenance in multiple myeloma: certainties and
103. Attal M, Harousseau JL, Marit G, Caillot D,
myeloma: results of a qualitative and quantitative
controversies. J Clin Oncol. 2009;27(32):e186-
Stoppa AM, Benboubker L. Lenalidomide after
analysis [abstract]. Blood. 2010;116(21):Abstract
e187.
autologous transplantation for myeloma: first
861.
110. McCarthy PL, Owzar K, Anderson KC, et al.
analysis of a prospective, randomized study of
106. Mihelic R, Kaufman JL, Lonial S. Maintenance
Phase III intergroup study of lenalidomide versus
the Intergroupe Francophone Du Myelome (IFM
therapy in multiple myeloma. Leukemia. 2007;
placebo maintenance therapy following single
2005 02) [abstract]. Blood. 2009;114(22):Abstract
21(6):1150-1157.
autologous hematopoietic stem cell transplanta-
529.
107. Spencer A, Prince HM, Roberts AW, et al. Con-
tion for multiple myeloma: CALGB 100104 [ab-
104. Cavo M, Perrone G, Buttignol S, et al.
solidation therapy with low-dose thalidomide and
stract]. Blood. 2010;116(21):Abstract 37.
Bortezomib-thalidomide-dexamethasone com-
prednisolone prolongs the survival of multiple my-
111. Attal M, Lauwers WC, Marit G, et al. Maintenance
pared with thalidomide-dexamethasone as induc-
eloma patients undergoing a single autologous
treatment with lenalidomide after transplantation
tion and consolidation therapy before and after
stem-cell transplantation procedure. J Clin Oncol.
for myeloma: final analysis of the IFM 2005-02
double autologous transplantation in newly diag-
2009;27:1788-1793.
[abstract]. Blood. 2010;116(21):Abstract 310.
nosed multiple myeloma: results from a random-
108. Stewart AK, Trudel S, Bahlis NJ, et al. A random-
112. Moreau P, Pylypenko HV, Grosicki S, et al. A
ized phase III study [abstract]. Blood. 2010;
ized phase III trial of thalidomide and prednisone
phase 3 prospective randomized international
116(21):Abstract 42.
as maintenance therapy following autologous
study (MMY-3021) comparing subcutaneous and
105. Terragna C, Zamagni E, Petrucci MT, et al. Mo-
stem cell transplantation in patients with multiple
intravenous administration of bortezomib in pa-
lecular remission after bortezomib-thalidomide-
myeloma: the NCIC CTG MY.10 trial [abstract].
tients with relapsed multiple myeloma [abstract].
dexamethasone compared with thalidomide-
Blood. 2010;116(21):Abstract 39.
Blood. 2010;116(21):Abstract 312.

---