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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;
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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
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
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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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.
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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Stem-cell transplantation
Median survival
(months)
Stage I
62
Stage II
Stage III
29
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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)
CR+PR: 63%
CR+VGPR: 44%
CR+nCR: 8%
200 mg/day placebo continuously; 40 mg dexamethasone on days 14, 912, and 1720; 40
mg dexamethasone on days 14 (maintenance treatment)
CR+PR: 46%
CR+VGPR: 16%
CR+nCR: 23%
CR+PR: 72%
CR+nCR: 7%
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%
CR+PR: 81%
CR+VGPR: 54%
CR: 15%
223; 65
CR+PR: 82%
CR+nCR: 52%
Event-free survival:
2-year overall survival: 75%
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%
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%
CR+PR: 89%
CR+nCR: 22%
CR+PR: 71%
CR+nCR : 9%
92;
CR+PR: 93%
CR+nCR: 38%
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
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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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n; age (years)
Response
Result
129; 72
CR+PR: 760%
PR: 604%
CR: 155%
126; 72
CR+PR: 476%
PR: 452%
CR: 24%
CR+PR: 89%
VGPR: 47%
CR: 13%
CR+PR: 37%
VGPR: 7%
CR: 2%
CR+PR: 83%
VGPR: 43%
CR: 18%
Palumbo et al (2006)
86
Facon et al (2007)87
Phase III, multicentre, randomised; 12 6-week cycles
116; 72
OR: 68%
PR: 21%
VGPR: 17%
CR:14%
nCR: 17%,
115; 72
OR: 51%
PR: 22%
VGPR: 14%
CR: 7%
nCR: 8%
CR+PR: 810%
VGPR: 476%
CR: 238%
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)
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
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n; age (years)
Response
Result
CR+PR: 89%
CR: 32%
CR+PR: 82%
CR: 35%
CR+PR: 50%
CR: 5%
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
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n; age (years)
Response
Result
169; 40%
were >60
CR+PR: 30%
CR: 2%
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%
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%
53; 64 (range
3686)
CR+PR: 60%
CR+nCR: 5%
Time to progression:
82 months
Overall survival: 175 months
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
35; 59
(range 3876)
CR+PR: 14%
CR+nCR: 0%
Duration of response: 23
months
Progression-free survival:
4 months
Overall survival: 27 months
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)
176; 62
(range 3585)
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n; age (years)
Response
Result
176; 63
(range 3384)
175; 64
(range 4082)
193; 60
(range 3484)
CR+PR+MR:
35%
CR+PR: 28%
CR+nCR: 12%
28; 64 (SD )
CR+PR: 37%
CR+nCR: 19%
26; 60 (SD )
CR+PR: 50%
CR+nCR: 4%
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
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
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
322; 62
(range 3488)
CR+PR: 43%
CR+nCR 11%
Time to progression:
65 months
Duration of response:
69 months
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
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Thalidomide
Bortezomib and dexamethasone
Bortezomib and doxorubicin
Without adverse characteristics
Previous treatment
Lenalidomide
Bortezomib
Renal impairment
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
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