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Seminar

Multiple myeloma
Marc S Raab, Klaus Podar, Iris Breitkreutz, Paul G Richardson, Kenneth C Anderson
Lancet 2009; 374: 32439
Published Online
June 22, 2009
DOI:10.1016/S01406736(09)60221-X
LeBow Institute for Myeloma
Therapeutics and Jerome
Lipper Center for Multiple
Myeloma Research,
Dana-Farber Cancer Institute,
Harvard Medical School,
Boston, MA, USA (M S Raab MD,
K Podar MD, I Breitkreutz MD,
P G Richardson MD,
Prof K C Anderson MD);
Department of Medicine V,
University of Heidelberg
Medical Center, Heidelberg,
Germany (M S Raab); and
National Center of Tumor
Diseases and German Cancer
Research Center, Heidelberg,
Germany (M S Raab,
I Breitkreutz)
Correspondence to:
Prof Kenneth C Anderson,
LeBow Institute for Myeloma
Therapeutics and Jerome Lipper
Multiple Myeloma Center,
Dana-Farber Cancer Institute,
Harvard Medical School,
44 Binney Street, Boston,
MA 02115, USA
Kenneth_Anderson@dfci.
harvard.edu

Multiple myeloma is characterised by clonal proliferation of malignant plasma cells, and mounting evidence indicates
that the bone marrow microenvironment of tumour cells has a pivotal role in myeloma pathogenesis. This knowledge
has already expanded treatment options for patients with multiple myeloma. Prototypic drugs thalidomide,
bortezomib, and lenalidomide have each been approved for the treatment of this disease by targeting both multiple
myeloma cells and the bone marrow microenvironment. Although benet was rst shown in relapsed and refractory
disease, improved overall response, duration of response, and progression-free and overall survival can be achieved
when these drugs are part of rst-line regimens. This treatment framework promises to improve outcome not only
for patients with multiple myeloma, but also with other haematological malignancies and solid tumours.

Introduction
The rst successful myeloma treatmenta combination
of melphalan and prednisonewas introduced in the
late 1960s, and was further improved by high-dose drug
regimens with autologous stem-cell transplantation in
the 1980s. However, the new era of treatment for multiple
myeloma was not initiated until the late 1990s with the
introduction of thalidomide, its analogue lenalidomide,
and bortezomib. We summarise the fundamental
therapeutic changes that these novel drugs have brought
for patients with early-stage multiple myeloma, those
with relapsed and refractory disease, and for elderly
patients. However, these drugs also have several doselimiting side-eects, and most patients eventually
relapse. Continuing preclinical studies therefore aim to
further delineate pathophysiological mechanisms specic
to multiple myeloma for identication of additional
targeted treatments to enhance tumour cytotoxicity, avoid
drug resistance, and improve patient outcome.

Epidemiology
Multiple myeloma is the second most frequent malignancy
of the blood in the USA after non-Hodgkin lymphomathe disease causes about 1% of neoplastic diseases
and 13% of haematological malignancies. Median age at
diagnosis is about 62 years for men and 61 years for women
(range 2092); only 2% of patients are younger than
40 years. About 20 000 cases occur every year in the USA;

Search strategy and selection criteria

See Online for webappendix

324

We searched Medline and PubMed using the terms multiple


myeloma, transplantation, targeted OR conventional
therapy, novel drugs, microenvironment, angiogenesis,
and cell adhesion, for reports published between October,
2003, and November, 2008. We also searched online accessible
abstract collections for annual meetings (200408) of the
American Society of Hematology (ASH), American Society of
Clinical Oncology (ASCO), and European Society of
Hematology (EHA). All international journals providing
abstracts in English were included, and articles were ranked
according to the impact factor of the journal. Case reports were
excluded. The date of the last search was Nov 21, 2008.

the incidence adjusted for age and ethnic group is 71 per


100 000 in men and 46 per 100 000 in women. The
incidence varies globally from 1 per 100 000 people in
China, to about 4 per 100 000 people in most developed
countries. Occurrence of the disease is more common in
men than women, and is twice as high in black than in
white American people.1,2 The reason for the uneven race
and sex distribution is unknown. Median survival after
conventional treatments is 34 years; high-dose treatment
followed by autologous stem-cell transplantation can
extend median survival to 57 years.3 Novel drugs, for use
alone and in combination with existing treatments, are
increasingly being assessed for ability to further improve
survival.4,5

Pathogenesis
Multiple myeloma is characterised by excess bone marrow
plasma cells, monoclonal protein, osteolytic bone lesions,
renal disease, and immunodeciency. A multistep
development model suggests that monoclonal gammopathy of undetermined clinical signicance might progress to smouldering multiple myeloma, and ultimately to
symptomatic intramedullary and extramedullary multiple
myeloma, or plasma cell leukaemia.6,7
Oncogenomic studies show that few dierences exist
between monoclonal gammopathy of undetermined
signicance and multiple myeloma,8,9 which underscores
the essential role of the bone marrow microenvironment
in development, maintenance, and progression of
multiple myeloma. Direct interactions between multiple
myeloma cells and bone marrow stromal cells, or between
extracellular matrix proteins of multiple myeloma cells,
are mediated through cell surface receptorseg,
integrins, cadherins, selectins, syndecans, and the
immunoglobulin superfamily of cell adhesion molecules.
Both types of interactions directly increase growth,
survival, migration, and drug resistance of multiple
myeloma cells, and modulate functions of bone marrow
stromal cells (ie, by enhancing cytokine secretion).
The non-cellular compartment of the bone marrow is
composed of extracellular matrix proteins and uid
(webappendix pp 14). Adhesion of multiple myeloma
cells to extracellular matrix proteinseg, collagen,
bronectin, laminin, and vitronectintriggers cell
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Cytokine-induced
signalling

Au
toc
rin
e

survival and drug resistance,10 and production and


secretion of urokinase-type plasminogen activator,
metalloproteinase-2, and metalloproteinase-9.11 The uid
consists of cytokines and growth factors such as
interleukin 6, VEGF, IGF1, members of the TNFsuperfamily, TGFB1, CCL3, SCF, HGF, and interleukin
10, which are produced and secreted by cells in the bone
marrow microenvironment, including multiple myeloma
cells, and are regulated by autocrine and paracrine loops
(gure 1) (webappendix pp 56).12,13
In the cellular bone marrow compartment, multiple
myeloma cells interact with haemopoietic and nonhaemopoietic cells (gure 2), which causes immune
suppression and lytic bone lesions. In turn, bone marrow
stromal cells send signals (directly through cell-cell
contact or indirectly through secretion of soluble factors),
which aect multiple myeloma cell growth, survival,
migration, and drug resistance. For example, integrinmediated adhesion of multiple myeloma cells to bone
marrow cells induces upregulation of cell cycle regulatory
proteins (eg, CCND), antiapoptotic proteins (eg, BCL2,
BCL2L1, and MCL1), and telomerase activity14 in multiple
myeloma cells, and NFB-dependent transcription and
secretion of interleukin 6 in bone marrow cells.15
Interleukin 6 secreted by bone marrow cells enhances
the production and secretion of VEGF by multiple
myeloma cells, and vice versa.
Multiple myeloma stem cells are a very small subset of
multiple myeloma cells, which reside in either the
osteoblastic or the endothelial niche, and can self-renew
and dierentiate.16,17 Drug-dependent modication of the
stem cell niche to block engraftment of multiple myeloma
stem cells, without inhibiting development of
haemopoietic stem cells, is a target for continuing
research. Mesenchymal stem cells could also be targeted
therapeutically; in patients with multiple myeloma, these
cells have decreased ability to inhibit T-cell proliferation,18
and produce high concentrations of interleukin 6 (the
most potent multiple myeloma growth factor), DKK1 (an
inhibitor of osteoblast dierentiation that is associated
with typical myeloma bone lesions), and factors that
are associated with angiogenesis and osteogenic
dierentiation.19
Induction of pro-angiogenic molecules (eg, VEGF)
enhances microvascular density in the bone marrow, and
accounts for the abnormal structure of multiple myeloma
tumour vessels. Mosaic blood vessels consist of
endothelial cells, highly proliferative circulatory
endothelial progenitors, haemopoietic stem cells,
haemopoietic progenitor cells, monocytes and
macrophages, and tumour cells (eg, multiple myeloma
cells).2022 Increased microvascular density correlates with
disease progression and poor prognosis; moreover,
variable blood ow and vessel leak results in lowered
drug delivery. Published ndings suggest that multiple
myeloma has specic endothelial cells (gure 1).
However, whether the endothelial cells are disease

IL6, VEGF, IGF1


CXCL12, TNFSF13B,
TNF-, HGF, CCL3

SFK

Parac
rin

RAS

CAV1
RAF

PRKC
PIK3/AKT

Cytokine and
growth-factor
secretion

Proliferation
Survival
Migration
Drug resistance

MAP2K1
NFB

JAK/STAT3

Non-multiple
myeloma cells

MAPK

Adhesion-mediated
Integrins
signalling
Selectins
Cadherins
Proteoglycans (eg, SDC1)
Immunoglobulins

VEGF, TNF-, HGF, IL3

Figure 1: Signalling cascades


IL=interleukin. SFK=SRC family of kinases.

intrinsic or converted from healthy endothelial cells by


tumour cells is unknown, and strategies to selectively
target these cells are under investigation.23
The medullar microenvironment of the bone marrow
is aected by the functionally distinct cortical bone.
Osteolytic bone lesions and osteoporosis are diagnosed
by metastatic bone surveys, CT, uorodeoxyglucose-PET,
and MRI in more than 90% of patients with multiple
myeloma, and are associated with bone pain and
fractures. These complications are caused by increased
osteoclast formation and activity, reduced numbers of
osteoblasts,24 and development of haemopoietic25 and
multiple myeloma stem cells (webappendix pp 79).
Haemopoietic stem cells reside in environments that
favour stem-cell dierentiation and mobilisationthe
quiescent osteoblastic or endosteal niche, or the active
endothelial niche.

Genetics
Multiple myeloma has a substantial and expanding
foundation of research into the genetic basis for the
disease. Cytogenetics and uorescent in-situ hybridisation
have shown that numeric abnormalities occur in the
genes of multiple myeloma cells in both a nonhyperdiploid and a hyperdiploid pattern (webappendix
p 10). Non-hyperdiploid abnormalities are associated
with reduced life-span because of high-risk translocations
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Seminar

Bone marrow

Bone

Macrophage

BMSC

Osteoclast

Myeloid
progenitor

ECM
T cell
HSC
MMSC?

B cell
Osteoblast

Lymphoid
progenitor

Diagnosis

EC
CEP
NK cell
Cellular haemopoietic

Osteoblast
progenitor

DC
Cellular non-haemopoietic

Figure 2: Interactions of multiple myeloma cells with the cellular haemopoietic and non-haemopoietic bone
marrow compartments
By aecting the bone marrow, multiple myeloma cells disrupt homoeostasis of stromal cells (haemopoietic cells,
non-haemopoietic cells) with one another and the extracellular matrix. Tumour cells thereby induce both direct and
indirect signalling sequalae in the bone marrow, which in turn supports multiple myeloma cell proliferation,
survival, migration, and drug resistance; adverse immune regulation; tumour angiogenesis; and increased boneresorbing activity. BMSC=bone marrow stem cell. CEP=circulatory endothelial progenitor. DC=dendritic cell.
EC=endothelial cell. ECM=extracellular matrix. HSC=haemopoietic stem cell. MMSC=multiple myeloma stem cell.
NK=natural killer.

of IGHR (t[4;14] or t[14;16]), partial (q14) or complete loss


of chromosome 13, and partial loss of chromosome 17
(p13). By comparison, hyperdiploid abnormalities caused
by multiple trisomies, and low frequency of monosomy
or deletion of chromosome 13 and translocation of IGHR
(t[11;14]) are associated with improved outcome
(lengthened survival).26 Primary early onset reciprocal
chromosomal translocations most frequently occur at
IGHR on chromosome 14 (q32.33), which is usually
juxtaposed to CCND1 (t[11;14][q13;q32.33]), CCND3
(t[6;14][p21;q32.33]), MAF (t[14;16][q32.33;23]), FGFR3
and WHSC1 (t[4;14][p16.3;q32.33]), and MAFB t[14;20]
[q32.33;q11.1]).6,27,28
Secondary late onset translocations and gene mutations
that have been implicated in disease progression are:
complex karyotypic abnormalities of MYC ;7,29,30 activation
of NRAS, KRAS, and FGFR3 mutations; inactivation of
mutations or deletions of TP53, RB1, and PTEN; and
inactivation of cyclin-dependent kinase inhibitors
CDKN2A and CDKN2C.31,32 Study ndings support a key
role of the constitutively activated NFKB pathway in
pathogenesis of multiple myeloma.33
Gene expression proling, array comparative genomic
hybridisation, and spectral karyotyping and multiplex
uorescence in-situ hybridisation have conrmed and
extended results from conventional cytogenetics and
uorescence in-situ hybridisation. These techniques
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have allowed prognostic classication and insights into


the pathogenesis of multiple myeloma, on the basis of
genetic abnormalities (webappendix pp 1112).34,35 Pathogenesis is aected by epigenetic gene silencing and
activation, and continuing clinical trials aim to assess
the promising results of early preclinical studies with
histone deacetylase inhibitors to inhibit multiple
myeloma cell survival (webappendix pp 56).36
Continuing research should improve and integrate
cytogenetic, genetic, and epigenetic data to further
delineate the molecular events needed for development
and progression of disease. Furthermore, generation of
readily accessible databases will help to identify diverse
patient categories and to tailor treatments to
individuals.37

Multiple myeloma is diagnosed from: the presence of


paraprotein in serum or urine, detected by serum
electrophoresis and immunoxation; inltration of
malignant plasma cells in the bone marrow, assessed by
bone marrow aspirate; and bone lesions, screened by
skeletal survey and MRI. Sirohi and Powles38 have
extensively reviewed the signs, diagnostic techniques,
and complications related to multiple myeloma.
The International Myeloma Working Group have
established criteria to distinguish asymptomatic
(smoldering) multiple myeloma, without immediate
need of treatment, from active disease, when treatment
is essential (panel).39 The main indicators for treatment
are signs of end-organ damage including hypercalcaemia,
renal insuciency, anaemia, and bone lesions.39
Until 2005, disease stage was classied according to
the DurieSalmon system.40 However, between 1981 and
2002, data from 10 750 patients with multiple myeloma
from Europe, the USA, Canada, and Asia were used to
formulate the new International Staging System
(table 1).41 This system provides improved prognosis
from readily available tests of serum concentrations of
2-microglobulin and albumin. It has been validated in
several clinical trials, and is undergoing assessment for
prognostic value with additional biological factors.

Disease management
Therapeutic targets
Initial treatment of multiple myeloma has changed
substantially as a result of drug development.42 Novel
therapeutic targets identied from pathogenesis of the
disease are multiple myeloma cells, bone marrow stromal
cells, endothelial cells, genes (eg, FGFR343), cytokines and
growth factors, and specic signalling pathways (KRAS,
RAF1, MAP2K1, PIK3, and AKT; JAK and STAT3; PRKC;
NFKB; and WNT) (gure 2; webappendix pp 56 and
10).44 For example, the drugs thalidomide, lenalidomide
and bortezomib have been validated by several phase III
trials in newly diagnosed multiple myeloma. These drugs
are able to overcome the supportive eects of the bone
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marrow microenvironment and have substantially


changed treatment strategies during the past 5 years.
Other preclinical drugs have been designed to inhibit
either transport of ubiquitinated proteins to the
aggresome, such as tubacin, or histone deacetylase, such
as LBH589 and vorinostat. Combined inhibition of
proteasomal and aggresomal degradation of ubiquitinated
proteins induces synergistic cytotoxic eects against
multiple myeloma cells in the bone marrow, which will
help to design clinical studies.45
Multiple myeloma bone disease is managed with
bisphosphonates such as pamidronate and zoledronic
acid, which inhibit bone resorption, but might also
inhibit proliferation of multiple myeloma cells.46 Adverse
eects of bisphosphonates include renal toxic eects
and osteonecrosis of the jaw.47 Bone disease can also be
treated with bortezomib, which inhibits osteoclasts and
stimulates osteoblasts, thereby increasing bone
formation,48 and in mice has been shown to induce
mesenchymal stem cells to preferentially undergo
dierentiation into osteoblasts, resulting in increased
ectopic ossicle and bone formation.49
Assessment of additional drugs with increased potency
and potentially reduced toxic eectseg, anti-angiogenic
drugs (bevazicumab, sorafenib, and pazopanib) and
endothelially-targeted drugs (debrotide)has indicated
that these drugs are more active when combined with
conventional or novel treatments for multiple
myeloma.5053

did conventional chemotherapy (5-year overall survival


52% vs 12%; mortality 3% for both treatments).54 This
study group was rst to show better 7-year event-free
survival from tandem stem-cell transplantation (two
sequential transplants) than from one transplantation, at
least for patients who had not achieved complete
response, broadly dened as no disease activity
detectable, after the rst transplantation.55
Barlogie and colleagues56 total therapy approach, in
which all available methods of treatment were
incorporated into front-line treatment, similarly showed
that tandem stem-cell transplantation was better than
conventional chemotherapy, especially in patients
achieving complete response with median disease-free
survival of 50 months and median overall survival of
7 years. Integration of novel drugs into these transplant
regimens has further improved results, but the acute and
cumulative toxic eects of total therapy restricts use to
only a subset of patients.

Stem-cell transplantation

Newly diagnosed disease

Substantial improvements in progression-free and


overall survival have been achieved by the introduction
of high-dose drug treatment followed by stem-cell
transplantation. In 1996, a randomised trial by
Intergroupe Francophone du Mylome showed that
stem-cell transplantation resulted in signicantly more
disease-free individuals and better overall survival than

Thalidomide has been used for cancer treatment because


of its anti-angiogenic activity. The drug has been
extensively studied in patients with newly diagnosed,
relapsed, and refractory multiple myeloma, both before
stem-cell transplantation and as maintenance treatment
after transplant. A phase III trial57 showed increased
response to combination treatment of thalidomide and
dexamethasone versus dexamethasone alone, and
subsequently, combined thalidomide and dexamethasone
was approved by the US Food and Drug Administration
(FDA) for patients with newly diagnosed disease.
The most common side-eects of thalidomide in
patients with all stages of disease are deep vein
thrombosis, constipation, peripheral neuropathy, and
fatigue, which often restrict dose and treatment duration
in preference to drug eectiveness.58 For example, up to
50% of patients on thalidomide develop peripheral
neuropathy, which manifests with signs of sensory
disorder (eg, distal paresthesia, hyperesthesia, and motor
disorder) and autonomic dysfunction, and usually
improves with reduction of dose and treatment
duration,59 such that thalidomide use should be kept to a
minimum.60 A consensus paper has recommended
aspirin prophylaxis for patients receiving thalidomide
who have only one other risk factor for
thrombosis including old age (>65 years of age), central

Panel: CRAB criteria for active multiple myeloma


C: hyercalcaemia
Calcium concentration >025 mmol/L (>05 mg/dL) above
normal range or >275 mmol/L (>105 mg/dL)
R: renal insuciency
Creatinine concentration >173 mmol/L (>2 mg/dL)
A: anaemia
Haemoglobin concentration 20 g/L below normal range
or <100 g/L
B: bone lesions
Lytic bone lesions of osteoporosis with compression fractures
Other features
Symptomatic hyperviscosity, amyloidosis, recurrent bacterial
infections (>2 per year)

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Concentration of components in serum

Median survival
(months)

Stage I

2-microglobulin 35 mg/L and albumin


35 g/dL

62

Stage II

2-microglobulin <35 mg/L and albumin


44
<35 g/dL, or 2-microglobulin 3555 mg/L

Stage III

2-microglobulin >55 mg/L

29

Table 1: International Staging System

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catheter, diabetes, cardiac disease, immobilisation,


hyperviscosity related to multiple myeloma, or other prothrombotic factors (eg, inherited thrombophilia).61
Therapeutic doses of warfarin and prophylactic doses of
low molecular weight heparin are recommended for

patients with more than one risk factor, especially in


patients receiving combination treatment of thalidomide
with doxorubicin or dexamethasone.62
Table 2 shows selected clinical trials of novel drugs in
transplant-eligible patients. Three randomised trials of

n; age (years)

Response

Result

200 mg/day thalidomide continuously; 40 mg dexamethasone on days 14, 912, and 1720;
40 mg dexamethasone on days 14 (maintenance treatment)

235; 64 (SD 103)

CR+PR: 63%
CR+VGPR: 44%
CR+nCR: 8%

Time to progression: 226 months


Overall survival:

200 mg/day placebo continuously; 40 mg dexamethasone on days 14, 912, and 1720; 40
mg dexamethasone on days 14 (maintenance treatment)

235; 644 (SD 96)

CR+PR: 46%
CR+VGPR: 16%
CR+nCR: 23%

Time to progression: 64 months


Overall survival:

200400 mg/day thalidomide continuously; 9 mg/m doxorubicin on days 14; 40 mg


dexamethasone on days 14, 912, and 1720

201; 56 (range 3665)

CR+PR: 72%
CR+nCR: 7%

04 mg vincristine on days 14; 9 mg/m doxorubicin on days 14; 40 mg dexamethasone on


days 14, 912, and 1720

201; 57 (range 3765)

CR+PR: 54%
CR+nCR: 3%

04 mg vincristine on day 1; 40 mg/m liposomal doxorubicin on day 1; 40 mg dexamethasone 115; 64 (range 3574)
on days 14, 912, and 1720

CR+PR: 63%
CR+VGPR: 31%
CR: 12%

2-year progression-free survival: 45%


2-year overall survival: 65%

200 mg/day thalidomide continuously; 04 mg vincristine on day 1; 40 mg/m liposomal


doxorubicin on day 1; 40 mg dexamethasone on days 14, 912, and 1720

117; 625 (range 4073)

CR+PR: 81%
CR+VGPR: 54%
CR: 15%

2-year progression-free survival: 59%


2-year overall survival: 77%

25 mg lenalidomide on days 121; 40 mg dexamethasone on days 14, 912, and 1720

223; 65

CR+PR: 82%
CR+nCR: 52%

Event-free survival:
2-year overall survival: 75%

25 mg lenalidomide on days 121; 40 mg dexamethasone on days 1, 8, 15, and 22

222; 65

CR+PR: 70%
CR+nCR: 42%

Event-free survival:
2-year overall survival: 87%

Rajkumar et al (2008)63
Phase III, multicentre, randomised, double-blind, placebo-controlled; four 4-week cycles

Lokhorst et al (2008)64
Phase III, multicentre, randomised; three 4-week cycles

Zervas et al (2007)65
Phase III, multicentre; four 4-week cycles

Rajkumar et al (2007)66
Phase III, multicentre, randomised; 4-week cycles

Zonder et al (2007)67
Phase III, multicentre, randomised, double-blind, placebo-controlled; three 5-week cycles, then 4-week cycles until disease progression or toxic eects
For rst three cycles, 25 mg lenalidomide on days 128; 40 mg dexamethasone on days 14,
912, and 1720. For next cycle (maintenance treatment), 25 mg lenalidomide on days 121;
40 mg dexamethasone on days 14 and 1518

61; 65

CR+PR: 85%
CR: 22%

1-year progression-free survival: 77% 1-year


overall survival: 93%

For rst three cycles, 25 mg placebo on days 128, ; 40 mg dexamethasone on days 14, 912,
and 1720. For next cycle (maintenance treatment, 25 mg placebo on days 121;
40 mg dexamethasone on days 14 and 1518

72; 65

CR+PR: 51%
CR: 4%

1-year progression-free survival: 55%


1-year overall survival: 91%

13 mg/m bortezomib on days 1, 4, 8, and 11; 40 mg dexamethasone on days 14 and 912

112; range <65

CR+PR: 89%
CR+nCR: 22%

1-year progression-free survival: 93%


1-year overall survival: 97%

04 mg vincristine on days 14; 9 mg/m doxorubicin on days 14); 40 mg dexamethasone on


days 14, 912, and 1720

110; range <65

CR+PR: 71%
CR+nCR : 9%

1-year progression-free survival: 90%


1-year overall survival: 95%

13 mg/m bortezomib on days 1, 4, 8, and 11; 200 mg/day thalidomide continuously; 40 mg


dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12

92;

CR+PR: 93%
CR+nCR: 38%

200 mg/day thalidomide continuously; 40 mg dexamethasone on days 14 and 912

95;

CR+PR: 79%
CR+nCR: 7%

Harousseau et al (2007)68
Phase II, multicentre, randomised; four 3-week cycles

Cavo et al (2007)69
Phase III, multicentre, randomised; three 3-week cycles

Data are number of patients (n), mean (SD), median, or percentage of patients, unless otherwise indicated. Thalidomide, dexamethasone, and lenalidomide were given orally; doxorubicin, vincristine, and
bortezomib were given intravenously. Placebo was given in the same way as the drug under investigation. CR=complete response (no disease activity detectable). PR=partial response (at least 50%
reduction in disease activity). VGPR=very good partial response. nCR=near complete response. CR, PR, VGPR, and nCR were dened according to Blade70 and Durie,71 and their colleagues. =data unavailable.

Table 2: Selected clinical trial regimens and outcomes with novel drugs for transplant eligible, newly diagnosed patients

328

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combination treatment in patients with newly diagnosed


disease, before stem-cell transplantation, have shown
better response with combined thalidomide and
dexamethasone, or combined thalidomide, dexamethasone, and doxorubicin, than with conventional chemotherapy, such as high-dose dexamethasone or VAD
(doxorubicin, vincristine, and intermittent high-dose
dexamethasone).57,6365 Two trials showed signicantly
increased response to the new combination treatments.63,65
In one of these trials,64 patients receiving induction
treatment with thalidomide had signicantly better
partial and complete response than did controls who did
not receive thalidomide, both before and after high-dose
chemotherapy. However, another trial has reported that
combined thalidomide and dexamethasone versus VAD
showed no benet to response after stem-cell
transplantation.72
Barlogie and colleagues73 have shown in a phase III
trial that addition of thalidomide to tandem stem-cell
transplantation led to better complete response than had
controls who did not receive thalidomide (62% vs 43%,
p<0001) and improved 5-year event-free survival (56% vs
44%, p=001). However, overall survival after relapse did
not improve, possibly because of increased drug
resistance and cumulative toxic eects.73
Lenalidomide is an immunomodulatory drug with
higher potency than has thalidomide, and without
sedative and neurotoxic adverse eects. The most
common side-eect is myelosuppression, which is
usually reversible with dose reduction and growth factor
support.74 A large randomised trial for newly diagnosed
multiple myeloma suggested that lenalidomide in
combination with low-dose dexamethasone (40 mg on
days 1, 8, 15, and 22, 4-week cycle) results in signicantly
better progression-free and overall survivial at 1 and
2 years than does lenalidomide with conventional highdose dexamethasone (40 mg on days 14, 912, and
1721, 4-week cycle), because of reduced toxic eects
with the low-dose regimen.66 Early results from another
study showed that combined lenalidomide and
dexamethasone improved progression-free survival and
response (overall and complete response) compared with
conventional high-dose dexamethasone alone.67
Lenalidomide decreases peripheral CD34+ stem-cell
concentration to a greater extent than does thalidomide.75
Therefore, early harvesting and use of cyclophosphamide
and granulocyte-colony stimulating factor is recommended to achieve sucient stem-cell yield. Preliminary
reports suggest that lenalidomide is able to overcome the
poor prognosis conferred by chromosome 13 deletion,76
whereas thalidomide seems to be less eective;77 however,
long term follow-up for event-free and overall survival
are not yet dened. Risk of deep vein thrombosis is an
important side-eect, especially for lenalidomide in
combination with dexamethasone, and prophylactic
strategies, such as those outlined for thalidomide, should
be used.61,62
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The boronic dipeptide bortezomib is a rst-in-class


proteasome inhibitor, which targets the proteasome to
prevent intracellular protein degradation. This
mechanism causes the cell cycle to arrest, anti-angiogenic
eects, induction of the stress response, and apoptosis of
multiple myeloma cells mediated by CASP8 and CASP9.78
Most common side-eects are peripheral neuropathy,
transient thrombocytopenia, fatigue, and gastrointestinal
disorders (constipation, nausea, and diarrhoea).
Data from a large randomised trial68 by Intergroupe
Francophone du Mylome in patients with newly
diagnosed disease showed improved overall response
and duration of response with combined bortezomib and
dexamethasone induction versus VAD. The result was
consistent both before and after high-dose melphalan
and autologous stem-cell transplantation; need for
second transplantation decreased and the role for
consolidative chemotherapy with DCEP (dexamethasone,
cyclophosphamide, etoposide, and cisplatin) was not
additive.68 However, data on progression-free and overall
survival after an extended follow-up are needed.
Of patients given VTD (bortezomib, thalidomide, and
dexamethasone) before transplantation, at least
60% achieved very good partial response versus 25% of
those given combined thalidomide and dexamethasone
(p<0001); near complete or complete response was
achieved in 38% of patients versus 7% (p=0007).69 VTD
also overcame the potential eect of adverse cytogenetics
on response, whereas combined thalidomide and dexamethasone did not.
Findings of a large multicenter phase I/II study
suggested that 100% of patients responded, 71% had very
good partial response or better, and 36% had near
complete or complete response, when combined
lenalidomide, bortezomib, and dexamethasone was used
for rst-line treatment.79 Induction treatment with
bortezomib in combination with dexamethasone or
doxorubicin (liposomal or PEGylated), or both, is also
highly active against multiple myeloma; results from
phase II/III studies showed an overall response of more
than 80%, and near complete or complete response of
1832%.8082
These data suggest that novel drugs in combination
with dexamethasone, with or without conventional
treatments, are better for induction treatment before
stem-cell transplantation than was use of conventional
treatments alone. Furthermore, incorporation of novel
drugs has also improved outcome for the total therapy
approach.83 Long-term follow-up of existing trials is
needed to establish the overall eect on survival from
incorporation of novel drugs into the transplant
framework. Nonetheless, approval of bortezomib and
combined thalidomide and dexamethasone for rst-line
treatment, indicates the eectiveness of novel drugs in
newly diagnosed patients.
Continuing clinical trials are assessing thalidomide,
bortezomib, and lenalidomide for maintenance treatment

For more on clinical trials see


http://clinicaltrials.gov

329

Seminar

after autologous stem-cell transplantation. Interferon


alpha had been regarded as the standard maintenance
treatment until the mid 1990s; however, a meta-analysis
of more than 4000 patients showed negligible eect on
survival.84 By contrast, two randomised studies83,85 have
shown that maintenance treatment with thalidomide is
benecial, both alone and in combination. Barlogie and
colleagues73 showed improved complete response and
5-year event-free survival with thalidomide, but no
improvement in overall survival. However, Attal and coworkers85 showed that thalidomide, compared with
observation, improved 3-year event-free survival (52% vs
36%) and 4-year overall survival (87% vs 77%).
For patients ineligible for stem-cell transplantation,
combined melphalan and prednisone has long been the
standard treatment. However, data from randomised
trials showed that the combination of melphalan and
prednisone with novel drugs (table 3), such as
thalidomide,8688 is better than melphalan and prednisone
alone is (mean response 80% vs 40%; event-free survival
28 months vs 15 months). By contrast, combined
thalidomide and dexamethasone is not better than
melphalan and prednisone is.89 Positive results have been
achieved with melphalan and prednisone combined with
lenalidomide (phase I/II)90 and bortezomib (phase II:
overall response 88%, complete response 32%, event-free
survival 27 months, and 3-year overall survival 85%).91
The large international randomised phase III trial VISTA
conrmed that addition of bortezomib to melphalan and
prednisone resulted in substantial improvement of
progression-free and overall survival, time to progression,
and overall and complete response, especially in highrisk patients (including those with adverse cytogenetics
and renal impairment), and with manageable toxic
eects.92 These results provided the framework for FDA
approval to treat newly diagnosed disease.
With the pronounced advances in extent and quality of
response, and associated clinical benet, emerging treatment strategies can be tailored to patients characteristics,
age, and risk factors. Bortezomib will be particularly
benecial since it seems to overcome the unfavourable
eect of serious or adverse prognostic factors, such as
unfavourable cytogenetics.92,93 To reduce the risk of deep
vein thrombosis in high-risk patients, combined
melphalan, prednisone, and bortezomib is preferable for
reduced thrombogenicity; whereas combined melphalan,
prednisone, and lenalidomide is preferable for patients
with increased risk of peripheral neuropathy.94

Relapsed, or relapsed and refractory disease


Dexamethasone was rst reported as a treatment for
patients with relapsed multiple myeloma by Alexanian
and co-workers,95 who recorded high inhibitory activity
with pulsed high-dose dexamethasone (40 mg daily,
consecutively for 4 days, beginning on days 14, 912, and
1720, 4-week cycle). This regimen has become a standard
for randomised trials to assess novel treatments for
330

relapsed and refractory disease. Conventional chemotherapeutic drugs have been used in combination with
dexamethasone to try to improve responseeg, VAD
achieved response in up to 65% of patients who were
resistant to alkylating drugs.96 Combined doxorubicin and
dexamethasone has been used with other drugs such as
melphalan, cyclophosphamide, carmustine, etoposide,
cisplatin, and thalidomide.9799 However, doxorubicin
increases risk of cardiomyopathy, and has to be given via
a central venous line; these issues have been partly
addressed by a PEGylated formulation of doxorubicin
with reduced cardiomyopathy risk, toxic eects on tissue,
and alopecia. Doxorubicin activity in combination with
dexamethasone has been slight, with almost all inhibition
of multiple myeloma attributable to dexamethasone.
Although stem-cell transplantation is a standard
treatment for young patients with newly diagnosed
multiple myeloma, this treatment approach was rst
introduced to overcome resistance to conventional
chemotherapy in patients with refractory disease.100
Several phase II trials have suggested a benet for
patients with primary refractory multiple myeloma101,102
and for patients with relapsed, chemo-sensitive disease,
who have median relapse-free survival of 2 years and
overall survival of 3 years.103 In relapsed and refractory
disease, stem-cell transplantation has resulted in
progression-free and overall survival of up to 11 and
19 months, respectively, but only at the cost of substantial
toxic eects and treatment-related mortality.100,104 Furthermore, patients with relapse after rst-line stem-cell
transplantation and favourable prognostic factors (eg,
more than 3 years remission since earlier transplant)
might benet from second transplantation.105
The optimum time for stem-cell transplantation is
debatable. Before the advent of novel drugs, Fermand
and co-workers106 compared rst-line stem-cell transplantation with transplantation as a rescue treatment after
rst relapse. Although a higher quality-of-life score with
improved progression-free survival was reported after
early stem-cell transplantation, overall survival was not
signicantly lengthened.106 This issue is being re-assessed
with novel drugs and targeted treatment.
In patients with primary refractory multiple myeloma
or those who have relapsed after rst-line treatment,
sequential stem-cell transplantation followed by nonmyeloablative allogeneic transplantation from HLAidentical siblings showed high occurrence of sustained
response, but occurrence of graft versus host disease was
high.107 Thus, patients who have relapsed after stem-cell
transplantation might benet from a rescue or nonmyeloablative allogeneic stem-cell transplantation
regimen,108,109 but this approach has led to poor outcomes
in heavily pretreated, or relapsed and refractory patients.110
Comparison of autologous tandem stem-cell transplantation with autologous then non-myeloablative
allogeneic transplantation was inconclusive.111 Therefore,
allogeneic stem-cell transplantation is recommended to
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Seminar

be done only in controlled clinical trials that aim to


exploit graft-versus-myeloma eect and keep attendant
toxic eects to a minimum.
Singhal and colleagues77 rst described successful use
of thalidomide (200800 mg daily) in patients with
relapsed and refractory multiple myeloma, and systematic
review of phase II trials reported partial or complete
response in 29% of patients.112 Use of thalidomide alone
is associated with low occurrence of deep vein thrombosis
(5% or less),113,114 but is complicated by accumulated and
dose-dependent toxic eects.58

Thalidomide-mediated inhibition of multiple myeloma


is enhanced by dexamethasone, both in vitro and in
clinical trials (51% of patients responded vs 29% for
thalidomide alone).115 However, combined thalidomide
and dexamethasone increases the risk of deep vein
thrombosis to 1015%.116118 Thus, prophylaxis with
aspirin, warfarin, or low-molecular-weight heparin is
recommended when thalidomide is given in combination
with other drugs.62
In view of the substantially improved response and
minimum myelosuppression with combined thalidomide

n; age (years)

Response

Result

100 mg/day thalidomide continuously; 4 mg/m melphalan on days


17; 40 mg/m prednisone on days 17; then 100 mg/day thalidomide
continuously (maintenance treatment)

129; 72

CR+PR: 760%
PR: 604%
CR: 155%

Overall survival: 450 months


Progression-free survival: 218 months

4 mg/m melphalan on days 17; 40 mg/m prednisone on days 17

126; 72

CR+PR: 476%
PR: 452%
CR: 24%

Overall survival: 476 months


Progression-free survival: 145 months

100400 mg/day thalidomide continuously; 025 mg/kg melphalan on


days 14; 2 mg/kg prednisone on days 14

122; range 6575

CR+PR: 89%
VGPR: 47%
CR: 13%

Overall survival: 516 months

025 mg/kg melphalan on days 14; 2 mg/kg prednisone on days 14

184; range 6575

CR+PR: 37%
VGPR: 7%
CR: 2%

Overall survival: 332 months

121; range 6575

CR+PR: 83%
VGPR: 43%
CR: 18%

Overall survival: 383 months

Palumbo et al (2006)

86

Phase III, multicentre; six 4-week cycles

Facon et al (2007)87
Phase III, multicentre, randomised; 12 6-week cycles

Phase III, multicentre, randomised; two 4-week cycles


04 mg vincristine on days 14; 9 mg/m doxorubicin on days 14;
40 mg dexamethasone on days 14, 912, and 1720; then two courses
of 100 mg/m melphalan, and stem-cell transplantation separated by 2
months
Hulin et al (2007)88
Phase III, multicentre, randomised, double-blind, placebo-controlled; 12 6-week cycles
100 mg/day thalidomide continuously; 02 mg/kg melphalan on
days 14; 2 mg/kg prednisone on days 14

113; 785 (range 7589) CR+PR: 69%


VGPR: 22%
CR: 7%

Overall survival: 453 months


Progression-free survival: 241 months

100 mg/day placebo continuously; 02 mg/kg melphalan on days 14; 2


mg/kg prednisone on days 14

116; 785 (range 7589) PR: 31%


VGPR: 7%
CR: 1%

Overall survival: 277 months


Progression-free survival: 190 months

116; 72

OR: 68%
PR: 21%
VGPR: 17%
CR:14%
nCR: 17%,

Event-free survival: 25 months


Overall survival: 45 months

115; 72

OR: 51%
PR: 22%
VGPR: 14%
CR: 7%
nCR: 8%

Event-free survival : 43 months


Overall survival: 58 months

53; 71 (range 5777)

CR+PR: 810%
VGPR: 476%
CR: 238%

1-year event-free survival: 92%


1-year overall survival: 100%

Ludwig et al (2007)89
Phase III, multicentre, randomised; 4-week cycles until best response
200 mg/day (up to 400 mg/day) thalidomide continuously; 40 mg
dexamethasone on days 14 and 1518 (odd cycles), or days 14
(even cycles)

Phase III, multicentre, randomised; 46-week cycles until best response


025 mg/kg melphalan on days 14; 2 mg/kg prednisone on days 14

Palumbo et al (2007)90
Phase I/II, multicentre; 9 4-week cycles
018025 mg/kg melphalan on days 14; 2 mg/kg prednisone on
days 14; 510 mg lenalidomide on days 121

(Continues on next page)

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331

Seminar

n; age (years)

Response

Result

60; 75 (range 6585)

CR+PR: 89%
CR: 32%

16-month event-free survival: 83%


16-month overall survival: 90%

344; 71 (range 5790)

CR+PR: 82%
CR: 35%

Time to progression: 240 months


Overall survival:

338; 71 (range 4891)

CR+PR: 50%
CR: 5%

Time to progression: 166 months


Overall survival:

(Continued from previous page)


Mateos et al (2006)91
Phase I/II, multicentre; four 6-week cycles
10 or 13 mg/m bortezomib on days 1, 4, 8, 11, 22, 25, 29, and 32;
followed by 10-day rest period; 9 mg/m melphalan on days 14;
60 mg/m prednisone on days 14
San Miguel et al (2008)92
Phase III, multicentre, randomised; four 6-week cycles, then ve 6-week cycles
For rst four cycles, 13 mg/m bortezomib on days 1, 4, 8, 11, 22, 25, 29,
and 32; 9 mg/m melphalan on days 14; 60 mg/m prednisone on days
14. For next ve cycles, 13 mg/m bortezomib on days 1, 8, 22, and 29;
9 mg/m melphalan on days 14; 60 mg/m prednisone on days 14
Phase III; nine 6-week cycles
9 mg/m melphalan on days 14; 60 mg/m prednisone on days 14

Data are number of patients (n), median, or percentage of patients, unless otherwise indicated. All drugs were given orally except bortezomib, which was given intravenously.
CR=complete response (no disease activity detectable). PR=partial response (at least 50% reduction in disease activity). VGPR=very good partial response. OR=overall response.
nCR=near complete response. CR, PR, VGPR, and nCR were dened according to Blade70 and Durie,71 and their colleagues.

Table 3: Selected clinical trial regimens and outcomes with novel drugs for transplant ineligible, newly diagnosed patients

and dexamethasone, this combination has been


incorporated into several other combination regimens
(table 4)eg, cyclophosphamide,120 cyclophosphamide
and etoposide,119 liposomal doxorubicin,128 and DT-PACE
(doxorubicin, cisplatin, cyclphosphamide, and etoposide).98 These combination regimens have achieved
response in 3276% of relapsed and refractory
patients.98,119,120,128
Early phase I trials with lenalidomide have shown
inhibition of multiple myeloma in heavily pretreated
patients without substantial somnolence, constipation,
or peripheral neuropathy.129 The recommended dose is
25 mg per day on the rst 21 days of a 4-week cycle.121,130
Subsequent phase III trials in patients with relapsed, or
relapsed and refractory disease reported signicantly
increased overall response (complete and partial
response), median time to progression, and overall
survival for patients on combined lenalidomide and
high-dose dexamethasone versus dexamethasone alone
(table 4);122,123 updated and pooled results showed
combination treatment increased overall survival from
31 to 35 months.131 With combination treatment, toxic
eects at grade three or four were neutropenia (41%122
and 30%123) and thromboembolic events (15%122 and
11%123), including deep vein thrombosis and pulmonary
embolus. Although neither trial required prophylactic
anti-thrombotic treatment, aspirin and additional anticoagulation drugs are recommended for combination
therapies with lenalidomide. On the basis of these
studies, combined lenalidomide and dexamethasone
was approved by the FDA for treatment of relapsed
multiple myeloma.122,123
After inhibition of multiple myeloma by intravenous
bortezomib was shown in a phase I trial,132 the drug was
tested in two multicentre phase II trialsSUMMIT124
332

and CREST125for relapsed and refractory disease


(table 4). These trials indicated that bortezomib
substantially lengthened overall survival, and
consequently, the drug was approved by the FDA and
European Medicines Agency for treatment of relapsed
and refractory disease.
Subsequently, extended follow-up (median 22 months)
of the randomised phase III APEX trial126 in relapsed
patients showed better response and overall survival for
patients on bortezomib than on high-dose
dexamethasone (table 4). The benet was evident despite
the fact that 62% of patients on the high-dose
dexamethasone later received bortezomib because
interim analyses showed that bortezomib had substantial
benet.133 Bortezomib is therefore the only drug that
when given alone provides lengthened survival and high
overall response for patients with relapsed disease.
These results led to FDA approval for treatment of
patients in rst relapse and beyond.
Specic management guidelines134 that recommend
treatment with bortezomib have reduced occurrence of
peripheral neuropathy, which is reversible in most
patients.135 Bortezomib has been assessed in
combination with other cytotoxic drugs. For example,
phase III combination of bortezomib with pegylated
liposomal doxorubicin resulted in signicantly
increased duration and frequency of response, time to
progression, and overall survival, compared with
bortezomib alone, and independent of the number of
lines of previous treatment (table 4).127,136 Patients who
had had previous disease progression on anthracyclinecontaining regimens (eg, doxorubicin) beneted from
combined bortexomib and doxorubicin, which is
consistent with reports from preclinical data that
bortezomib sensitises multiple myeloma cells to
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Seminar

chemotherapy.137 These results led to FDA approval of


combined bortezomib and doxorubicin for patients who
had not received bortezomib and had received at least
one line of previous treatment.
In addition to the expanded treatment options oered
by novel drugs, treatment of relapsed and refractory
multiple myeloma could now be improved by taking
account of individual patient characteristics such as
number of lines of previous treatment, old age, renal

disease, adverse cytogenetics (eg, chromosome 13


deletion), raised 2-microglobulin concentration, low
serum albumin concentration, advanced bone disease,
and extramedullary disease.138 For example, in patients
without specic adverse characteristics, combined
bortezomib and liposomal doxorubicin showed
improved time to progression versus bortezomib alone,
irrespective of previous treatments, including
anthracycline exposure or thalidomide treatment.136,139 By

n; age (years)

Response

Result

Key toxic eects

169; 40%
were >60

CR+PR: 30%
CR: 2%

2-year event-free survival:


20%
2-year overall survival: 48%

Grade >2: CNS 25%; gastrointestinal 16%;


peripheral neuropathy 9%

Grade >2 (data for both study groups):


tingling and numbness 19%;
constipation 18%; sedation 13%

Barlogie et al (2001)

113

Phase II
200800 mg/day thalidomide continuously

Palumbo et al (2004)118
Phase II, multicentre; 4-week cycles until disease progression
Patients with rst relapse: 100 mg/day
thalidomide continuously;
40 mg dexamethasone on days 14

62; 60

CR+PR: 56%

Progression-free survival:
17 months
3-year overall survival: 60%

Patients with second relapse: 100 mg/day


thalidomide continuously;
40 mg dexamethasone on days 14

58; 64

CR+PR: 46%

Progression-free survival:
11 months
Overall survival: 19 months

50; 41%
were >60

CR+PR: 65%
CR: 4%

Progression-free survival:
16 months
1-year overall survival: 63%

Grade 3: infectious complications 36%;


cardiovascular events 7%

53; 64 (range
3686)

CR+PR: 60%
CR+nCR: 5%

Time to progression:
82 months
Overall survival: 175 months

Grade 3: neutropenia 18%


Grade 4: neutropenia 8%

Moehler et al (2001)119
Phase II; three 4-week cycles
400 mg/day thalidomide continuously;
40 mg dexamethasone on days 14;
400 mg/m cyclophosphamide on days 14;
40 mg/m etoposide on days 14
Dimopoulos et al (2004)120
Phase II, multicentre; threesix 4-week cycles
400 mg/day thalidomide on days 15 and
1418; 20 mg/m dexamethasone on days
15 and 1418; 150 mg/m
cyclophosphamide every 12 h on days 15
Richardson et al (2006)121
Phase II, multicentre, randomised; 4-week cycles until relapse
30 mg lenalidomide continuously; 40 mg
dexamethasone on days 14 and 1518 for
suboptimum response

67; 60
(range 4090)

CR+PR: 18%
CR+nCR: 6%

Duration of response:
19 months
Progression-free survival:
8 months
Overall survival: 28 months

Grade 3: neutropenia 49%;


thrombocytopenia 15%; leukopenia 36%;
lymphopenia 31%; anaemia 15%
Grade 4: neutropenia 12%;
thrombocytopenia 16%; leukopenia 2%;
lymphopenia 6%; anaemia 2%

15 mg lenalidomide (twice daily) on days


121; 40 mg dexamethasone on days 14
and 1518 for suboptimum response

35; 59
(range 3876)

CR+PR: 14%
CR+nCR: 0%

Duration of response: 23
months
Progression-free survival:
4 months
Overall survival: 27 months

Grade 3: neutropenia 57%;


thrombocytopenia 26%; leukopenia 34%;
lymphopenia 31%; anaemia 11%
Grade 4: neutropenia 11%;
thrombocytopenia 17%; leukopenia 0%;
lymphopenia 9%; anaemia 3%

Weber et al (2007)122
Phase III, multicentre, randomised, placebo-controlled; 4-week cycles until relapse
25 mg lenalidomide on days 121;
40 mg dexamethasone on days 14, 912,
and 1720

177; 64
(range 3586)

CR+PR: 610% Time to progression:


CR: 141%
111 months
Overall survival: 296 months

Grade 3: neutropenia 412%; deep vein


thrombosis or pulmonary embolus 157%;
thrombocytopenia 147%; anaemia 130%;
pneumonia 114%; fatigue 62%

25 mg placebo on days 121; 40 mg


dexamethasone on days 14, 912,
and 1720

176; 62
(range 3585)

CR+PR: 199% Time to progression:


CR: 06%
47 months
Overall survival: 202 months

Grade 3: neutropenia 45%; deep vein


thrombosis or pulmonary embolus 34%;
thrombocytopenia 69%; anaemia 51%;
pneumonia 74%; fatigue 63%
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333

Seminar

n; age (years)

Response

Result

Key toxic eects

25 mg lenalidomide on days 121;


40 mg dexamethasone on days 14, 912,
and 1720

176; 63
(range 3384)

CR+PR: 602% Time to progression:


113 months
CR+nCR:
Overall survival: not reached at
159%
time of assessment

Grade 3: neutropenia 295%; deep vein


thrombosis 114%; thrombocytopenia
114%; anaemia 86%

25 mg placebo on days 121; 40 mg


dexamethasone on days 14, 912, and
1720

175; 64
(range 4082)

CR+PR: 240% Time to progression: 47


CR+nCR: 34% months
Overall survival: 207 months

Grade 3: neutropenia 23%; deep vein


thrombosis 46%; thrombocytopenia 57%;
anaemia 69%

193; 60
(range 3484)

CR+PR+MR:
35%
CR+PR: 28%
CR+nCR: 12%

Time to progression: 7 months


Overall survival: 16 months
Duration of response:
12 months

Grade 3: thrombocytopenia 28%;


neutropenia 11%; anaemia 8%; peripheral
neuropathy 12%; diarrhoea 7%; fatigue
121%
Grade 4: thrombocytopenia 3%;
neutropenia 3%; anaemia 0%;
peripheral neuropathy 0%; diarrhoea 1%;
fatigue <1%

(Continued from previous page)


Dimopoulos et al (2007)123
Phase III, multicentre; 4-week cycles until relapse

Richardson et al (2003)124 SUMMIT trial


Phase II, multicentre; eight 3-week cycles
13 mg/m bortezomib on days 1, 4, 8,
and 11;
20 mg dexamethasone on days 1, 2, 4, 5, 8,
9, 11, and 12 for suboptimum response

Jagganath et al (2004)125 CREST trial


Phase II, multicentre, randomised; eight 3-week cycles
10 mg/m bortezomib on days 1, 4, 8, and
11; 20 mg dexamethasone on days 1, 2, 4, 5,
8, 9, 11, and 12 for suboptimum response

28; 64 (SD )

CR+PR: 37%
CR+nCR: 19%

Overall survival: 27 months

Grade 34: neutropenia 11%;


thrombocytopenia 29%; pneumonia 0%;
fatigue 4%; peripheral neuropathy 8%

13 mg/m bortezomib on days 1, 4, 8, and


11; 20 mg dexamethasone on days 1, 2, 4, 5,
8, 9, 11, and 12 for suboptimum response

26; 60 (SD )

CR+PR: 50%
CR+nCR: 4%

Overall survival: 60 months

Grade 34: neutropenia 23%; thrombocytopenia 19%; pneumonia 4%; fatigue 12%;
peripheral neuropathy 15%

Time to progression:
62 months
Overall survival: 298 months
Duration of response:
78 months

Grade 3: thrombocytopenia 26%;


neutropenia 12%; anaemia 9%; peripheral
neuropathy 7%; diarrhoea 7%; fatigue 5%;
dyspnoea 5%
Grade 4: thrombocytopenia 4%;
neutropenia 2%; anaemia 1%; peripheral
neuropathy 1%; diarrhoea 0%; fatigue <1%;
dyspnoea <1%

Richardson et al (2005)126 APEX trial


Phase III, multicentre, randomised; eight 3-week cycles, then three 5-week cycles
For rst eight cycles, 13 mg/m bortezomib 333; 62
on days 1, 4, 8, and 11. For next three cycles, (range 4874)
13 mg/m bortezomib on days 1, 8, 15,
and 22

CR+PR: 43%
CR+nCR: 16%

Phase III, multicentre, randomised; four 5-week cycles, then ve 4-week cycles, for up to 40 weeks
For rst four cycles, 40 mg dexamethasone
on days 14, 912, and 1720. For next ve
cycles, 40 mg dexamethasone on days 14

336; 61
(range 4773)

CR+PR: 18%
CR+nCR: 1%

Time to progression:
35 months
Overall survival: 237 months
Duration of response:
56 months

Grade 3: thrombocytopenia 5%;


neutropenia 1%; anaemia 10%; peripheral
neuropathy 1%; diarrhoea 2%; fatigue 4%;
dyspnoea 3%
Grade 4: thrombocytopenia 1%;
neutropenia 0%; anaemia 1%; peripheral
neuropathy <1%; diarrhoea 0%;
fatigue <1%; dyspnoea 1%

Orlowski et al (2007)127
Phase III, multicentre, randomised; eight 3-week cycles
13 mg/m bortezomib on days 1, 4, 8,
and 11; 30 mg/m pegylated liposomal
doxorubicin on day 4

324; 61
(range 2885)

CR+PR: 48%
CR+nCR 14%

Time to progression:
94 months
Duration of response:
102 months

Grade 34: neutropenia 30%;


thrombocytopenia 22%; anaemia 9%;
diarrhoea 7%; asthenia 6%; fatigue 5%; hand
foot syndrome 5%

13 mg/m bortezomib on days 1, 4, 8,


and 11

322; 62
(range 3488)

CR+PR: 43%
CR+nCR 11%

Time to progression:
65 months
Duration of response:
69 months

Grade 34: neutropenia 14%;


thrombocytopenia 15%; anaemia 9%;
peripheral neuropathy 9%; neuralgia 5%

Data are number of patients (n), median, or percentage of patients, unless otherwise indicated. All drugs were given orally except cyclophosphamide, etoposide, and
bortezomib, which were given intravenously. All drugs were given once daily unless otherwise indicated. CR=complete response (no disease activity detectable). PR=partial
response (at least 5% reduction in disease activity). nCR=near complete response. MR=minimum response. CR, PR, VGPR, nCR, and MR were dened according to Blade70 and
Durie71, and their colleagues.

Table 4: Selected clinical trial regimens and outcomes with novel drugs in relapsed patients

334

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Seminar

Thalidomide
Bortezomib and dexamethasone
Bortezomib and doxorubicin
Without adverse characteristics

Previous treatment

Lenalidomide

Bortezomib

Lenalidomide and dexamethasone


Bortezomib and doxorubicin

Adverse prognostic characteristics*

Bortezomib and dexamethasone


Bortezomib and doxorubicin
Lenalidomide and dexamethasone

Renal impairment

Bortezomib and dexamethasone

Severe peripheral neuropathy

Lenalidomide and dexamethasone

Figure 3: Treatment considerations of relapsed and refractory disease


*Adverse characteristics such as short progression-free survival, extramedullary disease, immunoglobulin light chain disease, IgA isotype, and unfavourable cytogenetics.

contrast, treatment with lenalidomide and dexamethasone


in patients who had had previous thalidomide treatment,
resulted in a signicantly shorter time to progression
than did treatment in immunomodulatory-naive
patients.122,123 In elderly patients (>65 years of age),
bortezomib140 and lenalidomide141 are each safe and
eective, and although thalidomide seems to be eective
for rst-line treatment, reduced doses should be used
because of toxic eects.142 Both bortezomib143 and
thalidomide144 are safe and eective in patients with renal
impairment, but lenalidomide should be used with a
dose-reduction schedule in patients with clinically
signicant renal dysfunction because this drug is
cleared by the kidney. Conversely, for patients with
persistent peripheral neuropathy, a combination
treatment containing lenalidomide is preferred. Poor
prognosis from chromosome 13 deletion can be overcome
by bortezomib93 and lenalidomide,76 whereas thalidomide
is less eective.77 Furthermore, bortezomib can
overcome the poor prognosis from t(4;14), raised
2-microglobulin concentration, and low serum albumin
concentration; it is also active in patients with advanced
bone disease, plasmacytoma, and extramedullary
disease.140,145,146
Until now, partial deletion of chromosome 17 (p13) has
persisted as an adverse prognostic factor, and therefore
patients with this disorder should benet from
combinations of novel drugs and conventional treatments.
Combined bortezomib and dexamethasone (with or
without doxorubicin), or lenalidomide and dexamethasone
are most active and recommended for all patients with
relapsed and refractory disease (gure 3).138
Improved understanding of drug mechanisms and
preclinical studies have helped to identify drug
combinations to test in patients with relapsed, or relapsed
and refractory multiple myeloma, and potentially in newly
diagnosed patients. For example, two caspase-dependent
apoptotic pathways are activated in multiple myeloma
www.thelancet.com Vol 374 July 25, 2009

cells by bortezomib (mainly by CASP9 but also by CASP8)


and lenalidomide (CASP8), which led to a phase II trial147
of combined lenalidomide (15 mg daily), bortezomib
(10 mg/m2 on days 1, 4, 8, and 11), and dexamethasone
(20 mg daily on the day and day after bortezomib was
given). Treatment achieved an overall response (complete
and partial response) of 58%, and 36% of patients had
complete response, near complete response, or very good
partial response. Consequently, the combination was
tested in a phase I/II trial in newly diagnosed patients,79
with an overall response rate of 100% recorded and
favourable tolerability, such that this drug regimen could
become the standard treatment against which new drug
combinations might be tested in future clinical trials.

Conclusions
Thalidomide, lenalidomide, and bortezomib have
improved overall and duration of response, and
progression-free and overall survival, for patients with
newly diagnosed, and relapsed and refractory multiple
myeloma.148 Future randomised trials will establish the
durability of response to novel drugs in newly diagnosed
patients, and the benet of high-dose melphalan and stemcell transplantation in young patients. In relapsed patients,
continuing and future trials will test combinations of novel
drugs to increase eectiveness, overcome resistance, and
reduce toxic eects, so further improving patient
outcome.138
Contributors
MSR and KP contributed equally. MSR, KP, IB, PGR, and KCA reviewed
published work. MSR and KP extracted data. MSR, KP, and IB wrote the
report, and PGR and KCA revised the report. MSR, KP, IB, PGR, and KCA
contributed to the design of tables and gures. All authors approved the
nal version of the report.
Conicts of interest
KCA has received research funding from Celgene, Millennium
Pharmaceuticals, and Novartis. KCA is a member of the speakers bureaus
and advisory boards of Celgene, Millennium Pharmaceuticals, and
Novartis. PGR is a member of the speakers bureaus and advisory boards
335

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of Celgene, Millennium Pharmaceuticals, Genitum, and Johnson &


Johnson. All other authors declare that they have no conicts of interest.
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