The new england journal of medicine

review article

drug therapy

Multiple Myeloma
Robert A. Kyle, M.D., and S. Vincent Rajkumar, M.D.

From the Division of Hematology and Inter-

nal Medicine, Mayo Clinic, Rochester, Min-
nesota. Address reprint requests to Dr. Kyle
at the Division of Hematology and Internal
Medicine, Mayo Clinic, 200 First St. S.W.,
Rochester, MN 55905, or at kyle.robert@
m
promising.2
ultiple myeloma is a plasma-cell neoplasm that is charac-
terized by skeletal destruction, renal failure, anemia, and hypercalcemia.1
Although myeloma remains incurable, recent advances in its treatment, in-
cluding the use of thalidomide and new drugs such as bortezomib and CC-5013, are
mayo.edu.

N Engl J Med 2004;351:1860-73. diagnosis

Copyright © 2004 Massachusetts Medical Society.

The most common symptoms on presentation are fatigue, bone pain, and recurrent in-
fections.3 New diagnostic criteria require the presence of at least 10 percent plasma
cells on examination of the bone marrow (or biopsy of a tissue with monoclonal plas-
ma cells), monoclonal protein in the serum or urine, and evidence of end-organ dam-
age.4,5 The end-organ damage that meets the criterion for the diagnosis consists of hy-
percalcemia, renal insufficiency, anemia, or bone lesions (a group of findings referred
to as CRAB).4 Occasional patients presenting without a detectable monoclonal protein
but otherwise meeting these diagnostic criteria are considered to have nonsecretory
myeloma. The serum free light-chain assay is useful for monitoring many patients with
oligosecretory and nonsecretory myeloma. The differential diagnosis includes mono-
clonal gammopathy of undetermined significance (MGUS), smoldering (asymptom-
atic) multiple myeloma, primary amyloidosis, solitary plasmacytoma, low-grade lym-
phoma, chronic lymphocytic leukemia, and metastatic carcinoma.4
The median length of survival after diagnosis is approximately three years. Recent
advances have identified new prognostic markers, such as the complete deletion of
chromosome 13 or its long arm, as detected by karyotyping; the t(4;14) or t(14;16)
translocation; and increased density of bone marrow microvessels. These complement
established markers of adverse outcomes, such as an increase in the plasma-cell–label-
ing index, increased levels of serum beta2-microglobulin, low levels of serum albumin,
plasmablastic features in the bone marrow, and circulating plasma cells.6

pathophysiology
evolution of mgus
The first pathogenetic step in the development of myeloma is the emergence of a lim-
ited number of clonal plasma cells, clinically known as MGUS.7 Patients with MGUS
do not have symptoms or evidence of end-organ damage, but they do have an annual
risk of 1 percent of progression to myeloma or a related malignant disease.7 Approx-
imately 50 percent of patients have translocations that involve the immunoglobulin
heavy-chain locus on chromosome 14q32 and one of five partner chromosomes,
11q13 (CCND1) (the most common), 4p16.3 (FGFR-3 and MMSET), 6p21 (CCND3),

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 drug therapy

16q23 (c-maf ), and 20q11 (mafB).8,9 These and of nuclear factor-kB (NF-kB) ligand (RANKL) and
other cytogenetic changes (Fig. 1) are thought to a reduction in the level of its decoy receptor, os-
play an important role in the evolution of MGUS. teoprotegerin.12 The increase in the ratio of RANKL
to osteoprotegerin results in the activation of os-
progression to myeloma teoclasts and bone resorption. Overexpression of
With progression of MGUS to myeloma, complex RANKL is probably mediated in part by the release
genetic events occur in the neoplastic plasma cell of macrophage inflammatory protein 1a by neo-
(Fig. 1).8 Changes also occur in the bone marrow plastic plasma cells.13 Improved understanding of
microenvironment, including the induction of myeloma-associated bone disease has led to the use
angiogenesis, the suppression of cell-mediated of prophylactic bisphosphonate therapy.9
immunity, and the development of paracrine sig-
naling loops involving cytokines such as interleu- therapy
kin-6 and vascular endothelial growth factor.10,11
The resultant interactions of myeloma cells, bone There is no evidence that early treatment of asymp-
marrow stromal cells, and microvessels contribute tomatic (smoldering) multiple myeloma is bene-
to persistence of the tumor and its resistance to ficial.14,15 The median time from diagnosis to the
drugs.9,10 Understanding the cellular microenvi- progression to symptomatic disease is two to three
ronment in myeloma has had a role in the develop- years. Two recent studies suggest that thalidomide
ment of drugs such as thalidomide and bortezomib, may delay the time to progression.16,17 However,
which are able to overcome chemotherapy-resis- because some patients may remain progression-
tant disease.10 free for several years, therapy for asymptomatic my-
The development of bone lesions in myeloma eloma is not recommended, given the toxic effects
is thought to be related to an increase in the ex- of thalidomide. An approach to the treatment of
pression by osteoblasts of the receptor activator newly diagnosed myeloma is illustrated in Figure 2.

Genomic instability
Microenvironmental changes
in bone marrow
Translocations
at 14q32
Increased
(50%)
angiogenesis

Deletion of
chromosome 13
(50%)

Myeloma
Increased bone
resorption
Normal cell

Infection?
Inflammation?
N-RAS, K-RAS (30%)
p16 Methylation (40%)
Secondary translocations?
Monoclonal gammopathy
of undetermined significance

Figure 1. Mechanisms of Disease Progression in the Monoclonal Gammopathies.

Percentages are the proportions of patients with the abnormality. Microenvironmental changes include increased bone resorption — medi-
ated by increased production of receptor activator of nuclear factor-kB ligand, decreased levels of osteoprotegerin, and increased levels of
macrophage inflammatory protein 1a; the induction of angiogenesis; increased levels of interleukin-6 and vascular endothelial growth factor;
and decreased immune surveillance.

n engl j med 351;18 www.nejm.org october 28, 2004 1861

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 The new england journal of medicine

dexamethasone for three to four months as induc-

Eligible for Not eligible for tion therapy.19 Despite an acceptable response rate,
transplantation transplantation this therapy and similar intravenous regimens have
disadvantages, including the need for an indwelling
central venous line and the risk of catheter-relat-
Induction Dexamethasone Melphalan plus prednisone ed infections, thrombotic events, and alopecia. Fur-
Therapy or or thermore, the role of doxorubicin and vincristine
vincristine, other alkylator-based therapy
doxorubicin until plateau is reached in the regimen consisting of vincristine, doxorubi-
and dexamethasone cin, and dexamethasone is limited, because dexa-
or
thalidomide–dexamethasone*
methasone alone contributes to most of the activi-
ty (Table 1).
An alternative choice for induction is the oral
Stem-cell harvest
regimen of thalidomide plus dexamethasone. In
a recent trial, 50 patients with newly diagnosed my-
eloma were treated with this combination.28 Tha-
lidomide (at a dose of 200 mg per day) was given
with dexamethasone (at a dose of 40 mg per day)
Consolidation Autologous Melphalan plus prednisone on days 1 through 4, 9 through 12, and 17 through
Therapy transplantation or
thalidomide–dexamethasone* 20 (odd cycles) and on days 1 through 4 (even cy-
until plateau is reached cles). Each cycle was 28 days long, and there was
typically no gap between the cycles unless time was
Second autologous needed for the resolution of toxic effects. The re-
transplantation* sponse rate in the patients in this trial was 64 per-
or
mini–allogeneic
cent, which is similar to that in previous trials with
transplantation* the regimen of vincristine, doxorubicin, and dexa-
methasone. No important problems were found in
the collection or engraftment of stem cells in the
patients after receiving this induction therapy.28,34
Deep-vein thrombosis was an unexpected adverse
Maintenance No treatment or corticosteroids* or thalidomide* event in 12 percent of the patients in this trial. In a
Therapy separate trial, the response rate with this regimen
was 72 percent, and the use of prophylactic antico-
agulation with warfarin or low-molecular-weight
Figure 2. An Approach to the Treatment of Newly Diagnosed Multiple Myeloma. heparin prevented the occurrence of deep-vein
Induction therapy for patients eligible for transplantation is administered thrombosis.17 In a randomized trial comparing tha-
in four cycles before stem cells are harvested. The term “plateau” indicates
a minimum of 12 months of therapy and the achievement of stable disease
lidomide plus dexamethasone with dexamethasone
for at least 2 months. Asterisks denote investigational therapies. alone, the response rate with thalidomide plus dex-
amethasone was significantly better (P=0.01).35

induction therapy in patients not eligible

When possible, patients should be encouraged to for transplantation
participate in clinical trials at the time of diagnosis Patients who are not eligible for transplantation
and beyond. because of age, poor physical condition, or coexist-
ing conditions receive standard therapy with alkyl-
induction therapy in patients eligible ating agents.36 Although vincristine, doxorubicin,
for autologous stem-cell transplantation and dexamethasone, dexamethasone alone, or tha-
Patients who are eligible for autologous stem-cell lidomide plus dexamethasone can also be used as
transplantation are first treated with a regimen that initial therapy for these patients, the oral regimen
is not toxic to hematopoietic stem cells. The use of of melphalan plus prednisone is preferable in this
alkylating agents is best avoided, because they can setting to minimize toxic effects, unless there is a
prevent an adequate mobilization of stem cells.18 need for a rapid response, such as in patients with
Many physicians use vincristine, doxorubicin, and large, painful lytic lesions or with worsening renal

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 drug therapy

Table 1. Major Classes of Drugs Used in the Treatment of Myeloma.*

Drug
Alkylating agents
Melphalan and prednisone‡
Combinations, e.g., VBMCP§
Corticosteroids
Pulsed dexamethasone
VAD
Thalidomide and its analogues
Thalidomide
Thalidomide–dexamethasone
Melphalan–prednisone–
thalidomide
Cyclophosphamide–thalido-
mide–dexamethasone
CC-5013**
Bortezomib
Regimen and Usual Starting Dose Response Rate Trial
Newly
Diagnosed Relapsed
Disease Disease
percentage†
Repeated every 6 wk 50–55 — Myeloma Trialists’ Collaborative
Melphalan, 8–10 mg PO on days 1–7 Group20
Prednisone, 60 mg per day PO on days 1–7
Repeated every 5 wk 60 15¶ Myeloma Trialists’ Collaborative
Vincristine, 0.03 mg/kg (maximum 2 mg) IV Group,20 Cavo et al.21
on day 1
Carmustine, 0.5 mg/kg IV on day 1
Melphalan, 0.25 mg/kg PO on days 1–7
Cyclophosphamide, 10 mg/kg IV on day 1
Prednisone, 1 mg/kg PO on days 1–7
Repeated every 4–5 wk 45 25–35 Alexanian et al.,22 Alexanian et
Dexamethasone, 40 mg PO on days 1–4, al.23
9–12, and 17–20
Repeated every 4 wk 55–65 25–50 Alexanian et al.,19 Alexanian et
Vincristine, 0.4 mg per day IV continuous al.,22 Alexanian et al.24
infusion on days 1–4
Doxorubicin, 9 mg/m2 IV continuous infu-
sion on days 1–4
Dexamethasone, 40 mg PO on days
1–4, 9–12, and 17–20
Repeated every 4 wk 35 25–45 Rajkumar et al.,16 Weber et al.,17
200–400 mg PO on days 1–28 Singhal et al.,25 Kumar et al.,26
Juliusson et al.27
Repeated every 4 wk 65–70 50 Weber et al.,17 Rajkumar et al.,28
Thalidomide, 200 mg PO on days 1–28 Dimopoulos et al.29
Dexamethasone, 40 mg PO on days 1–4,
9–12, and 17–20¿
Repeated every 4 wk 80 — Palumbo et al.30
Melphalan, 4 mg/m2 PO on days 1–7
Prednisone, 40 mg/m2 PO on days 1–7
Thalidomide, 100 mg PO on days 1–28
Repeated every 3 wk — 75 Garcia-Sanz et al.31
Cyclophosphamide, 50 mg PO on days 1–21
Thalidomide, 200–800 mg PO on days 1–21
Dexamethasone, 40 mg PO on days 1–4
25–30 mg PO on days 1–21 every 28 days — 25 Richardson et al.32
1.3 mg/m2 on days 1, 4, 8, and 11 every 21 — 25 Richardson et al.33
days

* PO denotes orally; VBMCP vincristine, carmustine, melphalan, cyclophosphamide, and prednisone; VAD vincristine, doxorubicin, and dex-
amethasone; IV intravenous; mg/kg milligrams per kilogram of body weight; and mg/m2 milligrams per square meter of body-surface area.
† Percentages are estimates based on the results of all studies in which the given regimen was used.
‡ Appropriate trials of melphalan–prednisone in patients with relapsed or refractory disease who have not received alkylator therapy have not
been conducted.
§ Several drug combinations have been studied; VBMCP is the combination most commonly studied and used.
¶ The response rate reflects effectiveness in patients with relapsed or refractory disease and previous alkylator therapy.
¿ In one study, dexamethasone was administered on days 1–4, 9–12, and 17–20 in odd cycles and on days 1–4 in even cycles.
** CC-5013 is not commercially available.

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 The new england journal of medicine

function. Despite better response rates with any of
the more aggressive combination regimens than
with melphalan plus prednisone (Table 1), no sur-
vival benefit has been shown.20 Melphalan is gen-
erally administered at a dose of 8 to 10 mg per day
for 7 days (although lower doses may be needed in
patients with advanced renal failure) with predni-
sone at a dose of 60 mg per day orally during the
same 7 days, and both drugs are repeated every
6 weeks for a period of 12 to 18 months.36 The dos-
age of melphalan is adjusted to produce mild cy-
topenia at midcycle.
autologous stem-cell transplantation
Although not curative, autologous stem-cell trans-
plantation improves the likelihood of a complete
response, prolongs disease-free survival and over-
all survival, and is a major advance in myeloma ther-
apy (Table 2).46,47 The mortality rate is 1 to 2 per-
cent, and approximately 50 percent of patients can
be treated entirely as outpatients. Whether or not
a complete response is achieved is an important
predictor of the eventual outcome. Melphalan (at
a dose of 200 mg per square meter of body-surface
area) is the most widely used preparative regimen
for autologous stem-cell transplantation and is su-
perior to the older regimen of melphalan (140 mg
per square meter) combined with 8 Gy of total-
body irradiation.48 The data are limited on the ef-
fectiveness of autologous stem-cell transplanta-
tion in patients 65 years of age or older and those
with end-stage renal disease. However, the proce-
dure is feasible in these patients and can be under-
taken after careful consideration of the possible
risks and benefits, perhaps with the use of an in-
termediate dose of melphalan (100 mg per square
meter).49
The role of autologous stem-cell transplanta-
tion in the treatment of patients responding to in-
duction therapy has been questioned. In a Spanish
trial, patients responding to initial therapy had a
similar overall survival and progression-free surviv-
al with either autologous stem-cell transplantation
or eight additional courses of chemotherapy 39 —
suggesting that patients who benefit most from
autologous stem-cell transplantation are those with
disease refractory to induction therapy.50,51 The val-
ue of autologous stem-cell transplantation as ini-
tial therapy has also been challenged by the results
of three randomized trials that showed that trans- allogeneic transplantation
plantation can be safely delayed and used as salvage The advantages of allogeneic transplantation are
therapy at the time of relapse (Table 2).52
Generally, issues such as the inconvenience and
the adverse effects of prolonged chemotherapy and
difficulties in gaining the approval of health insur-
ance plans for cryopreservation of stem cells still
favor early autologous stem-cell transplantation.
This is especially the case for patients younger than
65 years of age with adequate renal function.46
tandem transplantation
In tandem (double) autologous stem-cell trans-
plantation, patients undergo a second planned au-
tologous stem-cell transplantation after they have
recovered from the first. Tandem transplantation
was developed by Barlogie and colleagues, to im-
prove complete-response rates.53,54 In a recent ran-
domized trial conducted in France, event-free sur-
vival and overall survival were significantly better
among recipients of tandem transplantation than
among those who underwent a single autologous
stem-cell transplantation (P=0.01)43 (Table 2). Con-
versely, preliminary data from three other random-
ized trials showed no convincing improvement in
overall survival among patients receiving tandem
transplantation, although the follow-up was too
short for definite conclusions to be drawn44,45,55
(Table 2). On the basis of the results of the French
trial, it is reasonable to consider tandem transplan-
tation for patients who do not have at least a very
good partial response (defined as a reduction of
90 percent or more in monoclonal protein levels)
with the first transplantation.43 However, until this
issue is resolved, it may be advantageous to collect
enough stem cells to allow a patient to undergo two
transplantations, reserving a second autologous
stem-cell transplantation for relapse.56
Two challenges persist. First, the current con-
ditioning regimens are inadequate. In an effort to
improve them, the use of bone-seeking radioac-
tive holmium and samarium is being tested.57,58
Second, reinfused hematopoietic stem cells are in-
evitably contaminated with tumor cells. Such con-
tamination can be reduced with the use of CD34
selection or the delivery of in vitro chemotherapy
to the collected stem cells. However, no effect on
overall survival has been observed to date, reflect-
ing the fact that residual drug-resistant cells in the
marrow are the principal cause of the recurrence
of disease.59,60
a graft that is not contaminated with tumor cells

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 Table 2. Results of Major Randomized Trials with Autologous Stem-Cell Transplantation in Myeloma.
Trial
Intergroupe Francophone
du Myélome 90
Medical Research Council
Myeloma VII
PETHEMA*
n engl j med 351;18
Myélome Autogreffe 91
www.nejm.org
Intergroup S9321
Myélome Autogreffe
october 28, 2004
Intergroupe Francophone du
Myélome 94
Copyright © 2004 Massachusetts Medical Society. All rights reserved.
Bologna 96
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Myélome Autogreffe 95
* PETHEMA denotes Programa para el Estudio y Tratamiento de las Hemopatías Malignas.
1865
Comparison
Conventional-dose chemotherapy vs.
autologous bone marrow trans-
plantation
Conventional-dose chemotherapy vs.
autologous stem-cell transplan-
tation
Conventional-dose chemotherapy vs.
autologous stem-cell transplan-
tation
Conventional-dose chemotherapy vs.
autologous stem-cell transplan-
tation
Conventional-dose chemotherapy vs.
autologous stem-cell transplan-
tation vs. allogeneic transplantation
Early vs. delayed autologous stem-cell
transplantation
Single vs. double autologous stem-cell
transplantation
Single vs. double autologous stem-cell
transplantation
Single vs. double autologous stem-cell
transplantation
No. of
Patients Outcome
200 Superior event-free survival and overall
survival with transplantation; 5-yr
survival, 52 percent with transplan-
tation vs. 12 percent with chemo-
therapy (P=0.03)
401 Superior progression-free survival and
overall survival with transplanta-
tion; median survival, 54 mo with
transplantation vs. 42 mo with che-
motherapy (P=0.04)
216 No difference in progression-free sur-
vival or overall survival; median
survival, 65 mo with transplanta-
tion vs. 67 mo with chemotherapy
190 No significant difference in event-free
survival or overall survival; median
survival, 55 mo with transplanta-
tion vs. 50 mo with chemotherapy
549 Median progression-free survival, 25
mo with autologous transplanta-
tion vs. 21 mo with chemotherapy
(P=0.05); no significant difference
in overall survival
185 Median event-free survival, 39 mo with
autologous transplantation vs. 13
mo with chemotherapy; no signifi-
cant difference in overall survival
399 Superior event-free survival and overall
survival with double transplantation;
7-yr survival, 42 percent with double
transplantation vs. 21 percent with
single transplantation (P=0.01)
220 Superior event-free survival with dou-
ble transplantation; no significant
difference in overall survival; medi-
an survival, 60 mo with double
transplantation vs. 56 mo with sin-
gle transplantation
230 No difference in progression-free or
overall survival
Comments Study
All patients <65 yr of age, all received Attal et al.37
interferon maintenance therapy,
and survival with chemotherapy
was shorter than expected
All patients <65 yr of age Child et al.38
Median age, 56 yr; only 164 patients re- Bladé et al.39
sponding to induction chemother-
apy underwent randomization
All patients 55–65 yr of age Fermand et al.40
drug therapy
After 39 patients were enrolled, alloge- Barlogie et al.41
neic transplantation group closed;
52 percent of patients assigned to
chemotherapy received salvage
transplantation at relapse
All patients <56 yr of age; early trans- Fermand et al.42
plantation associated with shorter
duration of chemotherapy and
symptoms
All patients <60 yr of age; benefit of Attal et al.43
second transplantation restricted
to those with less than very good
partial response to first
Interim analysis of first 220 patients Cavo et al.44
All patients <56 yr of age Fermand et al.45
 The new england journal of medicine

and a graft-versus-myeloma effect.61,62 However, ed that maintenance with prednisone may be use-
only 5 to 10 percent of patients are candidates for ful after conventional chemotherapy. The progres-
allogeneic transplantation when age, the availabil- sion-free survival was significantly longer with
ity of an HLA-matched sibling donor, and adequate 50 mg of oral, alternate-day prednisone (for a pe-
organ function are taken into consideration. Fur- riod of 14 months) than with 10 mg (for a period
thermore, the high rate of treatment-related death of 5 months; P=0.003). The overall survival was
has made conventional allogeneic transplanta- better with the use of the higher dose of predni-
tion unacceptable for most patients with myelo- sone, as compared with the lower dose (37 months
ma. T-cell–depleted transplants appear to be inef- and 26 months, respectively; P=0.05). It is unclear
fective.63 whether these results can be generalized, because
Several recent trials have used nonmyeloabla- this comparison study included only patients whose
tive conditioning regimens (also referred to as myeloma was responsive to corticosteroids and who
“mini” allogeneic transplantation).64 The greatest had not previously undergone autologous stem-cell
benefit has been reported in patients with newly di- transplantation. Clinical trials are under way to
agnosed disease who have first undergone autolo- evaluate novel approaches, such as the use of tha-
gous stem-cell transplantation to reduce the tumor lidomide and dendritic-cell vaccination as main-
burden and afterward undergone mini–allogeneic tenance therapy.
(nonmyeloablative) transplantation of stem cells
from an HLA-identical sibling donor.65 The rate of therapy for relapsed and refractory
treatment-related deaths was 15 to 20 percent with multiple myeloma
this strategy.66 There is also a high risk of both Almost all patients with multiple myeloma have
acute and chronic graft-versus-host disease, al- a risk of eventual relapse. If relapse occurs more than
though the emergence of these toxic effects ap- six months after conventional therapy is stopped,
pears to be necessary for disease control. Prelimi- the initial chemotherapy regimen should be re-
nary results from a French trial indicated that in instituted. Patients who have had stem cells cryopre-
patients with high-risk myeloma (those with a de- served early in the course of the disease can benefit
letion of chromosome 13 plus high levels of beta2- from the use of autologous stem-cell transplanta-
microglobulin), the overall survival with this ap- tion as salvage therapy.70
proach may not be superior to that with tandem The highest response rates in relapsed myelo-
autologous stem-cell transplantation.67 ma have been with the use of intravenous vincris-
Currently, the use of autologous stem-cell trans- tine, doxorubicin, and dexamethasone (Table 1).
plantation followed by mini–allogeneic transplan- Intravenous doxorubicin hydrochloride liposome
tation remains investigational and is best performed is a less cardiotoxic alternative to doxorubicin and
as part of a clinical trial. Outside that setting, we is being tested in patients with newly diagnosed
consider this option only for selected high-risk pa- disease.71 Dexamethasone alone is also effective.
tients with newly diagnosed disease who are young- Intravenous pulsed methylprednisolone (at a dose
er than 60 years of age and have HLA-identical sib- of 2 g three times per week) is an alternative to dex-
lings as potential donors, and for whom the current amethasone and may have fewer adverse effects.72
approaches appear to be futile (i.e., patients with In the past five years, major advances have been
karyotypic deletion of chromosome 13 or hypo- made with the use of thalidomide and the arrival of
diploidy, the t(4;14) or t(14;16) translocation, or novel approaches such as bortezomib. Depend-
a plasma cell–labeling index of 3 percent or more). ing on the clinical situation, these and other agents
(Table 1) are generally used sequentially, because
maintenance therapy disease refractory to one regimen or agent may re-
Initial trials of the usefulness of maintenance ther- spond to another.
apy with interferon alfa produced conflicting re-
sults, and the results of a meta-analysis showed thalidomide
only a modest improvement in overall survival.68
Recent results from an intergroup trial showed no Thalidomide was used as a sedative in the 1950s
apparent benefit from the use of interferon as main- and was withdrawn from the market after initial re-
tenance therapy.41 ports of teratogenicity in 1961.73 Subsequently, the
A study by Berenson and colleagues69 indicat- efficacy of thalidomide in erythema nodosum lep-

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 drug therapy
rosum, Behçet’s syndrome, the wasting and oral ul-
cers associated with the human immunodeficiency
virus syndrome, and graft-versus-host disease per-
mitted its use in clinical trials and for compassion-
ate use.74 In 1998, the Food and Drug Administra-
tion (FDA) approved the use of thalidomide in the
treatment of erythema nodosum leprosum.
clinical trials
Trials with thalidomide as an anticancer agent
were unsuccessful in the 1960s.75,76 However, the
finding of increased angiogenesis in myeloma cou-
pled with the recognition of the antiangiogenic
properties of thalidomide led to the first clinical
trial of this drug for the treatment of multiple my-
eloma, at the University of Arkansas. In that trial,
the rate of response was 25 percent in patients with
relapsed and refractory disease.25 Since then, sev-
eral studies have confirmed the activity of thalid-
omide in relapsed myeloma, with response rates
ranging from 25 percent to 35 percent.77-79 The re-
sponses are durable, with a median duration of ap-
proximately 12 months.26,77 Thalidomide had lim-
ited activity in extramedullary (soft-tissue) disease
in one study.80
Given the activity of thalidomide as a single
agent, subsequent trials explored its use in com-
bination with other active agents in the treatment
of relapsed myeloma. Response rates when tha-
lidomide was used with corticosteroids, as com-
pared with the rates with thalidomide alone, in-
creased to approximately 50 percent29,81-83 and to
more than 70 percent when used in a three-drug
combination of thalidomide, dexamethasone, and
an alkylating agent (either cyclophosphamide or
melphalan).31,79,84 Thalidomide alone or in com-
bination is now considered standard therapy for
relapsed and refractory myeloma. As discussed ear-
lier, this activity also has translated into the incor-
poration of thalidomide in the initial treatment
of multiple myeloma.
adverse effects
Sedation, fatigue, constipation, and rash are com-
mon adverse effects but usually are responsive to
dose reduction.85 Peripheral neuropathy occurs with
long-term use and often necessitates the discon-
tinuation of the therapy or a dose reduction. The
incidence of deep-vein thrombosis is only 1 to 3 per-
cent in patients receiving thalidomide alone but in-
creases to 10 to 15 percent in patients receiving the
drug in combination with dexamethasone and to
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about 25 percent in patients receiving the drug in
combination with other cytotoxic chemotherapeu-
tic agents, particularly doxorubicin.77,79,86-88 Other
adverse effects include edema, bradycardia, neutro-
penia, impotence, and hypothyroidism. The use of
thalidomide in pregnancy is absolutely contrain-
dicated, and the System for Thalidomide Educa-
tion and Prescribing Safety Program89 must be fol-
lowed to prevent teratogenic effects.
dosage
Thalidomide is usually administered in a dosage of
200 mg per day, which is increased to 400 mg per
day after two to four weeks, if tolerated. Lower dos-
es (50 to 100 mg) are being investigated, and to min-
imize long-term toxic effects, the dose should be
adjusted to the lowest level that can achieve and
maintain a response. Doses above 200 mg are gen-
erally not indicated when thalidomide is used in
combination with corticosteroids or chemotherapy.
mechanism of action
Thalidomide undergoes rapid interconversion be-
tween the R-enantiomer and the S-enantiomer and
spontaneous cleavage to more than 12 metabolites
in solutions at physiologic pH.90 Furthermore, its
activity in most in vitro assays is moderate or negli-
gible, and its effects in animal models are depen-
dent on the species and the route of administra-
tion. Thus, the study of its mechanism of action is
difficult.91 Proposed mechanisms include the in-
hibition of tumor necrosis factor a, the preven-
tion of free-radical–mediated DNA damage, the
suppression of angiogenesis, an increase in cell-
mediated cytotoxic effects, and the alteration of the
expression of cellular adhesion molecules.74 Tha-
lidomide may also inhibit the activity of NF-kB
and the enzymes cyclooxygenase-1 and cyclooxy-
genase-2 (Fig. 3).
bortezomib
Bortezomib (formerly known as PS-341) was the
first proteasome inhibitor to enter clinical trials. It
was granted accelerated approval by the FDA for
the treatment of advanced myeloma in May 2003.
clinical trials
In preclinical models, bortezomib showed sub-
stantial activity against many cancers, including
myeloma.92-96 Its promising efficacy against my-
eloma was noted in a phase 1 dose-finding study
october 28, 2004 1867
 The new england journal
Stromal cells
Thalidomide
Bortezomib
Thalidomide
Bortezomib
Tumor necrosis factor a
Interleukin-6
Alkylating agents
Corticosteroids Nuclear
Bortezomib factor-kB Bortezomib
Thalidomide
T cells
Thalidomide
Natural killer cells
Figure 3. Proposed Mechanism of Action of Drugs to Target the Myeloma Cell
and Components of the Bone Marrow Microenvironment.
In myeloma cells, alkylating agents, corticosteroids, and bortezomib inhibit
cell growth and induce apoptosis. The effect of bortezomib on myeloma cells
is mediated in part by the inhibition of nuclear factor-kB. Thalidomide and
bortezomib inhibit the interaction between myeloma cells and stromal cells
as well as the production of cytokines such as tumor necrosis factor a and
interleukin-6. Thalidomide inhibits angiogenesis and stimulates the immune-
surveillance properties of T cells and natural killer cells. Solid arrows indicate
stimulation or secretion and dashed arrows inhibition.
conducted by Orlowski and colleagues.97 On the
basis of these observations, a phase 2 multicenter
trial of intravenous bortezomib in myeloma was
initiated33 (the drug was given at a dose of 1.3 mg
per square meter over a period of three to five sec-
onds on days 1, 4, 8, and 11 in a 21-day cycle for a
maximum of eight cycles). Of 193 patients who
could be evaluated, 92 percent had received three
or more of the major classes of agents for myelo-
ma, and in 91 percent the disease had been re-
fractory to the most recent treatment. The partial-
response rate with bortezomib was 27 percent,
and 4 percent of patients achieved a complete re-
sponse.98 The median duration of response was
12 months, and the responses were associated with
improvement in cytopenia, renal function, and the
quality of life.99 Older age (above 65 years) and ex-
tensive marrow involvement were associated with
a lower rate of response.33,100
A randomized, phase 2 trial of bortezomib in
myeloma that had not responded to treatment or
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of medicine
had relapsed after the initial induction therapy and
consolidation therapy also was completed recent-
ly.101 In this trial, patients were randomly assigned
to receive one of two doses of bortezomib (28 pa-
tients were assigned to receive a dose of 1.0 mg per
square meter and 26 patients 1.3 mg per square
meter) administered on days 1, 4, 8, and 11 in a
21-day cycle for a total of eight cycles. Responses
occurred in 33 percent of those receiving 1.0 mg
per square meter and in 50 percent of those receiv-
ing 1.3 mg per square meter. Although initial trials
allowed a maximum of only eight cycles of bortez-
omib, recent data indicate that it is safe to admin-
ister at least an additional five or six cycles of ther-
apy without undue toxic effects.101 A recent phase
3 trial involving 670 patients and comparing bor-
tezomib with pulsed dexamethasone therapy was
closed early because of a longer time to disease pro-
gression in patients receiving bortezomib.102 In
trials to date, the response to bortezomib has been
shown to be rapid, usually occurring within one or
two cycles of the therapy.
Studies are under way of bortezomib in com-
bination with other effective agents. In the initial
phase 2 trial, dexamethasone was added to therapy
for 106 patients whose condition had not respond-
ed or those in whom the disease had progressed
while they were receiving bortezomib.33,103 In 19
of these patients (18 percent), there was a response
to the addition of dexamethasone with a reduction
of at least 25 percent in monoclonal protein levels,
suggesting an additive effect that can be exploit-
ed in future trials. Other investigators are studying
bortezomib in combination with thalidomide, peg-
ylated doxorubicin, and alkylating agents.104,105
adverse effects
The most common adverse effects of bortezomib
are gastrointestinal symptoms, cytopenia, fatigue,
and peripheral neuropathy.33,106 A decrease in the
platelet count to less than 50,000 per cubic milli-
meter occurs in almost 30 percent of patients. Pe-
ripheral neuropathy, often painful, develops in ap-
proximately 30 percent of patients and is more
frequent in those who have previously received neu-
rotoxic therapy and those with a preexisting neu-
ropathy.
dosing
The recommended starting dose is 1.3 mg per
square meter administered on days 1, 4, 8, and 11
of a 21-day cycle.33 Reductions to 1.0 mg per square
october 28, 2004
 drug therapy

meter or, if needed, to 0.7 mg per square meter may duction of at least 50 percent in monoclonal pro-
be necessary, depending on the toxic effects. tein levels in approximately 30 percent of patients
with relapsed myeloma, and myelosuppression was
mechanism of action the major dose-limiting toxic effect.114,115 A multi-
Bortezomib is a specific inhibitor of the 26S pro- center, randomized phase 2 study in which the sub-
teasome, a large intracellular adenosine triphos- jects had relapsed refractory myeloma was recently
phate–dependent protease responsible for protein completed,32 in which CC-5013 was administered
catabolism in all eukaryotic cells. Normally, cellular at a dose of 15 mg twice per day or a dose of 30 mg
proteins destined for catabolism are first ubiquit- once per day for a period of 3 weeks and was fol-
inated — a pathway in which C-terminal glycine res- lowed by a 1-week rest (in a 28-day cycle). The cycle
idues of ubiquitin molecules attach covalently to was repeated until disease progression or toxic ef-
specific lysine moieties on the protein.107 Ubiquit- fects occurred. In 24 percent of 83 patients who
inated proteins are identified and degraded in the could be evaluated, there was a reduction of at least
central portion of the proteasome, a pathway criti- 50 percent in monoclonal protein levels. The most
cal for normal cellular events to occur, including cell common adverse effects were grade 3 or higher
cycling, signal transduction, and transcriptional thrombocytopenia (i.e., a platelet count of less than
regulation. Inhibition of this pathway creates ma- 50,000 per cubic millimeter), which occurred in
jor imbalances in the levels of various regulatory 18 percent of patients, and neutropenia (i.e., a neu-
proteins, leading to arrest of the cell cycle and apo- trophil count of less than 1000 per cubic milli-
ptosis. meter), which occurred in 28 percent of patients.
The therapeutic effect of bortezomib-induced Adverse events were more frequent among those
inhibition of the proteasome in myeloma is prob- receiving 15 mg twice per day. Common adverse
ably a result of direct cytotoxicity and of effects on effects observed with thalidomide, however, such
the bone marrow microenvironment (Fig. 3).94,108 as sedation, constipation, and neuropathy, were not
One of the consequences of proteasome inhibi- observed. CC-5013 appears to be a promising agent
tion is the accumulation of IkB, an inhibitor of the for the treatment of myeloma, and trials conducted
major transcription factor NF-kB.109 At the cellu- for approval by the FDA are under way.
lar level, inhibition of NF-kB leads to a decrease
in the expression of adhesion molecules and vari- other novel agents
ous growth, survival, and angiogenic factors. It also
causes a decrease in the levels of the proteins that Several other agents, including 2-methoxyestra-
promote apoptosis, Bcl-2 and A1/Bfl-1, triggering diol, neovastat, oblimersen, farnesyltransferase,
the release of cytochrome-c, activation of caspase and histone deacetylase inhibitors, are being ac-
9, and apoptosis of myeloma cells.94 However, in- tively investigated.10,112 Preliminary evidence sug-
hibition of NF-kB is unlikely to be the sole mecha- gests that arsenic trioxide has clinical activity against
nism of the observed antimyeloma effects.92,94,110 myeloma,116 and trials are under way to confirm
this possibility and to determine optimal dosing.
cc-5013 Another thalidomide analogue, CC-4047, also has
shown activity.117
As a means to overcoming the nonhematologic tox-
ic effects of thalidomide, including teratogenicity, treatment of complications
several active analogues of thalidomide have been
developed. CC-5013 (lenalidomide) is an amino- Table 3 summarizes current management strate-
substituted variant of thalidomide that belongs to gies for complications observed in patients with my-
a class of analogues known as immunomodulatory eloma. Important advances include the prevention
drugs. Its preclinical activity is more potent and and treatment of hypercalcemia and bony lesions
more promising than the activity of thalidomide. with the monthly administration of bisphospho-
The drug induces apoptosis and decreases the bind- nates in patients with myeloma bone disease.118,119
ing of myeloma cells to stromal cells in bone mar- Such treatment may be complicated by albumin-
row.111 It also inhibits angiogenesis and promotes uria, renal dysfunction, and osteonecrosis of the
cytotoxicity mediated by natural killer cells.112,113 jaw. Another recent advance is the use of vertebro-
In two phase 2 trials of CC-5013, there was a re- plasty or kyphoplasty to reduce pain and help re-

n engl j med 351;18 www.nejm.org october 28, 2004 1869

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 The new england journal of medicine

Table 3. Treatment of Complications in Multiple Myeloma.

Complication Therapeutic Options

Myeloma bone disease Pamidronate or zoledronic acid in patients with documented bone disease
Encouragement of activity to prevent osteopenia and deep-vein thrombosis
Pain control with narcotic analgesics, if needed; avoidance of nonsteroidal antiinflam-
matory agents
Radiation to treat painful bony lesions refractory to pain medication or cord compression
Surgical intervention to prevent or treat pathologic fractures
Vertebroplasty or kyphoplasty for selected vertebral lesions, to reduce pain and improve
height
Anemia Treatment of reversible causes such as deficiencies of iron, B12, or folate
Erythropoietin for symptomatic anemia during chemotherapy
Transfusions as needed
Infections Vaccination against Streptococcus pneumoniae, Haemophilus influenzae, and influenza
Consideration of prophylactic broad-spectrum antibiotic therapy when corticosteroids
are used
Intravenous immune globulin for recurrent serious infections associated with hypogam-
maglobulinemia
Consideration of prophylaxis against Pneumocystis carinii when prolonged corticosteroid
therapy is used; avoidance of trimethoprim–sulfamethoxazole when thalidomide
is used
Hypercalcemia Intravenous fluids and corticosteroids
Bisphosphonates when hypercalcemia is severe or unresponsive to hydration and corti-
costeroids
Renal failure Correction of reversible causes such as dehydration, hypercalcemia, and hyperuricemia
Chemotherapy (e.g., vincristine, doxorubicin, and dexamethasone; dexamethasone
alone; or thalidomide–dexamethasone) for rapid control of disease
Alkaline diuresis for acute renal failure due to cast nephropathy; avoid alkalinization in
patients with hypercalcemia
Trial of plasma exchange in acute evolving renal failure
Hyperviscosity syndrome Plasma exchange for symptomatic patients (serum viscosity does not correlate well with
symptoms)

store vertebral height in patients with compression neously, one to improve rates of complete response
fractures. with the intense use of available methods, which is
aimed at finding a cure, and the other to exploit
future directions conventional and novel agents in an effort to con-
trol myeloma and convert it into a chronic indolent
Ongoing randomized trials promise to define fur- disease. Success in either direction would be mo-
ther the roles of new agents, mini–allogeneic trans- mentous.
plantation, and maintenance therapy. There is a Supported in part by grants from the National Cancer Institute
continuing search for active agents based on ad- (CA62242, CA85818, CA93842, CA107476, and CA100080), the Mul-
tiple Myeloma Research Foundation, and the Leukemia and Lym-
vances in understanding the biology of myelo- phoma Society.
ma.112 Microarray-based pharmacogenomic analy- Dr. Kyle reports having received consulting fees from NeoRx,
sis may usher in an era of therapy tailored to the Millennium, Aeterna, Celgene, and Novartis; and Dr. Rajkumar
consultation fees from Celgene and grants from Celgene and Mil-
individual patient. 120
lennium.
Finally, two paths are being explored simulta-

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