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The New England Journal of Medicine

Issue: Volume 351(18), 28 October 2004, pp 1860-1873
Copyright: Copyright © 2004 Massachusetts Medical Society. All rights reserved.
Publication Type: [Review Article]
ISSN: 0028-4793
Accession: 00006024-200410280-00009

[Review Article]

Drug Therapy: Multiple Myeloma

Kyle, Robert A.; Rajkumar, S. Vincent.

Author Information
From the Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota. 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@mayo.edu.
Multiple myeloma is a plasma-cell neoplasm that is characterized by skeletal destruction, renal failure, anemia,
and hypercalcemia. [1] Although myeloma remains incurable, recent advances in its treatment, including the use of
thalidomide and new drugs such as bortezomib and CC-5013, are promising. [2]

Diagnosis

The most common symptoms on presentation are fatigue, bone pain, and recurrent infections. [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 plasma cells), monoclonal protein in the serum or urine, and evidence of end-organ damage.
[4,5] The end-organ damage that meets the criterion for the diagnosis consists of hypercalcemia, 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 monoclonal gammopathy of undetermined significance (MGUS),
smoldering (asymptomatic) multiple myeloma, primary amyloidosis, solitary plasmacytoma, low-grade lymphoma,
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-labeling index, increased levels of serum
beta(2))-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 limited 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] Approximately
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),
16q23 (c-maf), and 20q11 (mafB). [8,9] These and other cytogenetic changes (Figure 1) are thought to play an
important role in the evolution of MGUS.

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 - mediated by increased
production of receptor activator of nuclear factor-(kappa)B ligand, decreased levels of osteoprotegerin, and
increased levels of macrophage inflammatory protein 1(alpha); the induction of angiogenesis; increased levels of
interleukin-6 and vascular endothelial growth factor; and decreased immune surveillance.

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Progression to Myeloma

With progression of MGUS to myeloma, complex genetic events occur in the neoplastic plasma cell (Figure 1). [8]
Changes also occur in the bone marrow microenvironment, including the induction of angiogenesis, the suppression of
cell-mediated immunity, and the development of paracrine signaling loops involving cytokines such as interleukin-6
and vascular endothelial growth factor. [10,11] The resultant interactions of myeloma cells, bone marrow stromal
cells, and microvessels contribute to persistence of the tumor and its resistance to drugs. [9,10] Understanding the
cellular microenvironment in myeloma has had a role in the development of drugs such as thalidomide and bortezomib,
which are able to overcome chemotherapy-resistant disease. [10]

The development of bone lesions in myeloma is thought to be related to an increase in the expression by
osteoblasts of the receptor activator of nuclear factor-(kappa)B (NF-(kappa)B) ligand (RANKL) and a reduction in the
level of its decoy receptor, osteoprotegerin. [12] The increase in the ratio of RANKL to osteoprotegerin results in the
activation of osteoclasts and bone resorption. Overexpression of RANKL is probably mediated in part by the release of
macrophage inflammatory protein 1(alpha) by neoplastic plasma cells. [13] Improved understanding of myeloma-
associated bone disease has led to the use of prophylactic bisphosphonate therapy. [9]

Therapy

There is no evidence that early treatment of asymptomatic (smoldering) multiple myeloma is beneficial. [14,15]
The median time from diagnosis to the progression to symptomatic disease is two to three years. Two recent studies
suggest that thalidomide may delay the time to progression. [16,17] However, because some patients may remain
progression-free for several years, therapy for asymptomatic myeloma is not recommended, given the toxic effects of
thalidomide. An approach to the treatment of newly diagnosed myeloma is illustrated in Figure 2. When possible,
patients should be encouraged to participate in clinical trials at the time of diagnosis and beyond.

Figure 2. An Approach to the Treatment of Newly Diagnosed Multiple Myeloma. Induction therapy for patients eligible
for transplantation is administered 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 for at least 2 months. Asterisks denote
investigational therapies.

Induction Therapy in Patients Eligible for Autologous Stem-Cell Transplantation

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Patients who are eligible for autologous stem-cell transplantation are first treated with a regimen that is not toxic
to hematopoietic stem cells. The use of alkylating agents is best avoided, because they can prevent an adequate
mobilization of stem cells. [18] Many physicians use vincristine, doxorubicin, and dexamethasone for three to four
months as induction therapy. [19] Despite an acceptable response rate, this therapy and similar intravenous regimens
have disadvantages, including the need for an indwelling central venous line and the risk of catheter-related
infections, thrombotic events, and alopecia. Furthermore, the role of doxorubicin and vincristine in the regimen
consisting of vincristine, doxorubicin, and dexamethasone is limited, because dexamethasone alone contributes to
most of the activity (Table 1).

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

An alternative choice for induction is the oral regimen of thalidomide plus dexamethasone. In a recent trial, 50
patients with newly diagnosed myeloma were treated with this combination. [28] Thalidomide (at a dose of 200 mg per
day) was given with dexamethasone (at a dose of 40 mg per day) on days 1 through 4, 9 through 12, and 17 through 20
(odd cycles) and on days 1 through 4 (even cycles). Each cycle was 28 days long, and there was typically no gap
between the cycles unless time was needed for the resolution of toxic effects. The response rate in the patients in
this trial was 64 percent, which is similar to that in previous trials with the regimen of vincristine, doxorubicin, and
dexamethasone. 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 event in 12 percent of the
patients in this trial. In a separate trial, the response rate with this regimen was 72 percent, and the use of
prophylactic anticoagulation with warfarin or low-molecular-weight heparin prevented the occurrence of deep-vein
thrombosis. [17] In a randomized trial comparing thalidomide plus dexamethasone with dexamethasone alone, the
response rate with thalidomide plus dexamethasone was significantly better (P=0.01). [35]

Induction Therapy in Patients Not Eligible for Transplantation

Patients who are not eligible for transplantation because of age, poor physical condition, or coexisting conditions
receive standard therapy with alkylating agents. [36] Although vincristine, doxorubicin, and dexamethasone,
dexamethasone alone, or thalidomide plus dexamethasone can also be used as initial therapy for these patients, the
oral regimen of melphalan plus prednisone is preferable in this setting to minimize toxic effects, unless there is a need
for a rapid response, such as in patients with large, painful lytic lesions or with worsening renal function. Despite
better response rates with any of the more aggressive combination regimens than with melphalan plus prednisone
(Table 1), no survival benefit has been shown. [20] Melphalan is generally 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 prednisone 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 dosage of melphalan is adjusted to produce mild cytopenia at midcycle.

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Autologous Stem-Cell Transplantation

Although not curative, autologous stem-cell transplantation improves the likelihood of a complete response,
prolongs disease-free survival and overall survival, and is a major advance in myeloma therapy (Table 2). [46,47] The
mortality rate is 1 to 2 percent, 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 superior 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 effectiveness of autologous stem-cell transplantation in
patients 65 years of age or older and those with end-stage renal disease. However, the procedure is feasible in these
patients and can be undertaken after careful consideration of the possible risks and benefits, perhaps with the use of
an intermediate dose of melphalan (100 mg per square meter). [49]

Table 2. Results of Major Randomized Trials with Autologous Stem-Cell Transplantation in Myeloma.

The role of autologous stem-cell transplantation in the treatment of patients responding to induction therapy has
been questioned. In a Spanish trial, patients responding to initial therapy had a similar overall survival and
progression-free survival 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 value of autologous stem-cell transplantation as initial therapy has also
been challenged by the results of three randomized trials that showed that transplantation can be safely delayed and
used as salvage 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 insurance 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 transplantation, patients undergo a second planned autologous stem-cell
transplantation after they have recovered from the first. Tandem transplantation was developed by Barlogie and
colleagues, to improve complete-response rates. [53,54] In a recent randomized trial conducted in France, event-free
survival 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). Conversely, preliminary data
from three other randomized 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 drawn [44,45,55] (Table
2). On the basis of the results of the French trial, it is reasonable to consider tandem transplantation 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 conditioning regimens are inadequate. In an effort to improve them, the
use of bone-seeking radioactive holmium and samarium is being tested. [57,58] Second, reinfused hematopoietic stem
cells are inevitably contaminated with tumor cells. Such contamination 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, reflecting the fact that residual drug-resistant cells in the marrow are the principal cause of the
recurrence of disease. [59,60]

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Allogeneic Transplantation

The advantages of allogeneic transplantation are a graft that is not contaminated with tumor cells and a graft-
versus-myeloma effect. [61,62] However, only 5 to 10 percent of patients are candidates for allogeneic
transplantation when age, the availability of an HLA-matched sibling donor, and adequate organ function are taken
into consideration. Furthermore, the high rate of treatment-related death has made conventional allogeneic
transplantation unacceptable for most patients with myeloma. T-cell-depleted transplants appear to be ineffective.
[63]

Several recent trials have used nonmyeloablative conditioning regimens (also referred to as "mini" allogeneic
transplantation). [64] The greatest benefit has been reported in patients with newly diagnosed disease who have first
undergone autologous stem-cell transplantation to reduce the tumor burden and afterward undergone mini-allogeneic
(nonmyeloablative) transplantation of stem cells from an HLA-identical sibling donor. [65] The rate of treatment-
related deaths was 15 to 20 percent with this strategy. [66] There is also a high risk of both acute and chronic graft-
versus-host disease, although the emergence of these toxic effects appears to be necessary for disease control.
Preliminary results from a French trial indicated that in patients with high-risk myeloma (those with a deletion of
chromosome 13 plus high levels of beta(2))-microglobulin), the overall survival with this approach may not be superior
to that with tandem autologous stem-cell transplantation. [67]

Currently, the use of autologous stem-cell transplantation followed by mini-allogeneic transplantation remains
investigational and is best performed as part of a clinical trial. Outside that setting, we consider this option only for
selected high-risk patients with newly diagnosed disease who are younger than 60 years of age and have HLA-identical
siblings as potential donors, and for whom the current approaches appear to be futile (i.e., patients with karyotypic
deletion of chromosome 13 or hypodiploidy, the t(4;14) or t(14;16) translocation, or a plasma cell-labeling index of 3
percent or more).

Maintenance Therapy

Initial trials of the usefulness of maintenance therapy with interferon alfa produced conflicting results, and the
results of a meta-analysis showed only a modest improvement in overall survival. [68] Recent results from an
intergroup trial showed no apparent benefit from the use of interferon as maintenance therapy. [41]

A study by Berenson and colleagues [69] indicated that maintenance with prednisone may be useful after
conventional chemotherapy. The progression-free survival was significantly longer with 50 mg of oral, alternate-day
prednisone (for a period of 14 months) than with 10 mg (for a period of 5 months; P=0.003). The overall survival was
better with the use of the higher dose of prednisone, as compared with the lower dose (37 months and 26 months,
respectively; P=0.05). It is unclear whether these results can be generalized, because this comparison study included
only patients whose myeloma was responsive to corticosteroids and who had not previously undergone autologous
stem-cell transplantation. Clinical trials are under way to evaluate novel approaches, such as the use of thalidomide
and dendritic-cell vaccination as maintenance therapy.

Therapy for Relapsed and Refractory Multiple Myeloma

Almost all patients with multiple myeloma have a risk of eventual relapse. If relapse occurs more than six months
after conventional therapy is stopped, the initial chemotherapy regimen should be reinstituted. Patients who have had
stem cells cryopreserved early in the course of the disease can benefit from the use of autologous stem-cell
transplantation as salvage therapy. [70]

The highest response rates in relapsed myeloma have been with the use of intravenous vincristine, doxorubicin,
and dexamethasone (Table 1). Intravenous doxorubicin hydrochloride liposome is a less cardiotoxic alternative to
doxorubicin and is being tested in patients with newly diagnosed disease. [71] Dexamethasone alone is also effective.
Intravenous pulsed methylprednisolone (at a dose of 2 g three times per week) is an alternative to dexamethasone and
may have fewer adverse effects. [72]

In the past five years, major advances have been made with the use of thalidomide and the arrival of novel
approaches such as bortezomib. Depending on the clinical situation, these and other agents (Table 1) are generally
used sequentially, because disease refractory to one regimen or agent may respond to another.

Thalidomide

Thalidomide was used as a sedative in the 1950s and was withdrawn from the market after initial reports of
teratogenicity in 1961. [73] Subsequently, the efficacy of thalidomide in erythema nodosum leprosum, Behcet's
syndrome, the wasting and oral ulcers associated with the human immunodeficiency virus syndrome, and graft-
versus-host disease permitted its use in clinical trials and for compassionate use. [74] In 1998, the Food and Drug
Administration (FDA) approved the use of thalidomide in the treatment of erythema nodosum leprosum.

Clinical Trials

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Trials with thalidomide as an anticancer agent were unsuccessful in the 1960s. [75,76] However, the finding of
increased angiogenesis in myeloma coupled with the recognition of the antiangiogenic properties of thalidomide led to
the first clinical trial of this drug for the treatment of multiple myeloma, 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, several studies
have confirmed the activity of thalidomide in relapsed myeloma, with response rates ranging from 25 percent to 35
percent. [77-79] The responses are durable, with a median duration of approximately 12 months. [26,77] Thalidomide
had limited 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 combination with other
active agents in the treatment of relapsed myeloma. Response rates when thalidomide was used with corticosteroids,
as compared with the rates with thalidomide alone, increased to approximately 50 percent [29,81-83] 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 combination is now considered standard therapy
for relapsed and refractory myeloma. As discussed earlier, this activity also has translated into the incorporation of
thalidomide in the initial treatment of multiple myeloma.

Adverse Effects

Sedation, fatigue, constipation, and rash are common adverse effects but usually are responsive to dose
reduction. [85] Peripheral neuropathy occurs with long-term use and often necessitates the discontinuation of the
therapy or a dose reduction. The incidence of deep-vein thrombosis is only 1 to 3 percent in patients receiving
thalidomide alone but increases to 10 to 15 percent in patients receiving the drug in combination with dexamethasone
and to about 25 percent in patients receiving the drug in combination with other cytotoxic chemotherapeutic agents,
particularly doxorubicin. [77,79,86-88] Other adverse effects include edema, bradycardia, neutropenia, impotence,
and hypothyroidism. The use of thalidomide in pregnancy is absolutely contraindicated, and the System for
Thalidomide Education and Prescribing Safety Program [89] must be followed 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 doses (50 to 100 mg) are being investigated, and to minimize 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 generally not indicated when thalidomide is used in combination with corticosteroids or chemotherapy.

Mechanism of Action

Thalidomide undergoes rapid interconversion between 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 negligible, and its effects in animal models are dependent on the species and the route of
administration. Thus, the study of its mechanism of action is difficult. [91] Proposed mechanisms include the inhibition
of tumor necrosis factor (alpha), the prevention 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] Thalidomide may also inhibit the activity of NF-(kappa)B and the enzymes cyclooxygenase-1 and
cyclooxygenase-2 (Figure 3).

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-(kappa)B.
Thalidomide and bortezomib inhibit the interaction between myeloma cells and stromal cells as well as the production
of cytokines such as tumor necrosis factor (alpha) 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

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dashed arrows inhibition.

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 substantial activity against many cancers, including myeloma. [92-96] Its
promising efficacy against myeloma was noted in a phase 1 dose-finding study conducted by Orlowski and colleagues.
[97] On the basis of these observations, a phase 2 multicenter trial of intravenous bortezomib in myeloma was initiated
[33] (the drug was given at a dose of 1.3 mg per square meter over a period of three to five seconds 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 myeloma, and in 91 percent the disease had been refractory
to the most recent treatment. The partial-response rate with bortezomib was 27 percent, and 4 percent of patients
achieved a complete response. [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
extensive 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 had relapsed after
the initial induction therapy and consolidation therapy also was completed recently. [101] In this trial, patients were
randomly assigned to receive one of two doses of bortezomib (28 patients 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 receiving 1.3 mg per square meter. Although initial trials allowed a maximum of only eight cycles of
bortezomib, recent data indicate that it is safe to administer at least an additional five or six cycles of therapy without
undue toxic effects. [101] A recent phase 3 trial involving 670 patients and comparing bortezomib with pulsed
dexamethasone therapy was closed early because of a longer time to disease progression 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 combination with other effective agents. In the initial phase 2 trial,
dexamethasone was added to therapy for 106 patients whose condition had not responded 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 exploited in future trials. Other investigators are studying bortezomib in
combination with thalidomide, pegylated 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 millimeter occurs in
almost 30 percent of patients. Peripheral neuropathy, often painful, develops in approximately 30 percent of patients
and is more frequent in those who have previously received neurotoxic therapy and those with a preexisting
neuropathy.

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 meter or, if needed, to 0.7 mg per square meter may be necessary, depending on
the toxic effects.

Mechanism of Action

Bortezomib is a specific inhibitor of the 26S proteasome, a large intracellular adenosine triphosphate-dependent
protease responsible for protein catabolism in all eukaryotic cells. Normally, cellular proteins destined for catabolism
are first ubiquitinated - a pathway in which C-terminal glycine residues of ubiquitin molecules attach covalently to
specific lysine moieties on the protein. [107] Ubiquitinated proteins are identified and degraded in the central portion
of the proteasome, a pathway critical for normal cellular events to occur, including cell cycling, signal transduction,
and transcriptional regulation. Inhibition of this pathway creates major imbalances in the levels of various regulatory
proteins, leading to arrest of the cell cycle and apoptosis.

The therapeutic effect of bortezomib-induced inhibition of the proteasome in myeloma is probably a result of
direct cytotoxicity and of effects on the bone marrow microenvironment (Figure 3). [94,108] One of the consequences
of proteasome inhibition is the accumulation of I(kappa)B, an inhibitor of the major transcription factor NF-(kappa)B.
[109] At the cellular level, inhibition of NF-(kappa)B leads to a decrease in the expression of adhesion molecules and
various growth, survival, and angiogenic factors. It also causes a decrease in the levels of the proteins that promote
apoptosis, Bcl-2 and A1/Bfl-1, triggering the release of cytochrome-c, activation of caspase 9, and apoptosis of
myeloma cells. [94] However, inhibition of NF-(kappa)B is unlikely to be the sole mechanism of the observed
antimyeloma effects. [92,94,110]

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CC-5013

As a means to overcoming the nonhematologic toxic effects of thalidomide, including teratogenicity, several
active analogues of thalidomide have been developed. CC-5013 (lenalidomide) is an amino-substituted variant of
thalidomide that belongs to a class of analogues known as immunomodulatory drugs. Its preclinical activity is more
potent and more promising than the activity of thalidomide. The drug induces apoptosis and decreases the binding of
myeloma cells to stromal cells in bone marrow. [111] It also inhibits angiogenesis and promotes cytotoxicity mediated
by natural killer cells. [112,113]

In two phase 2 trials of CC-5013, there was a reduction of at least 50 percent in monoclonal protein levels in
approximately 30 percent of patients with relapsed myeloma, and myelosuppression was the major dose-limiting toxic
effect. [114,115] A multicenter, randomized phase 2 study in which the subjects had relapsed refractory myeloma was
recently completed, [32] in which CC-5013 was administered at a dose of 15 mg twice per day or a dose of 30 mg once
per day for a period of 3 weeks and was followed by a 1-week rest (in a 28-day cycle). The cycle was repeated until
disease progression or toxic effects occurred. In 24 percent of 83 patients who could be evaluated, there was a
reduction of at least 50 percent in monoclonal protein levels. The most common adverse effects were grade 3 or
higher thrombocytopenia (i.e., a platelet count of less than 50,000 per cubic millimeter), which occurred in 18
percent of patients, and neutropenia (i.e., a neutrophil count of less than 1000 per cubic millimeter), which occurred
in 28 percent of patients. Adverse events were more frequent among those receiving 15 mg twice per day. Common
adverse effects observed with thalidomide, however, such as sedation, constipation, and neuropathy, were not
observed. CC-5013 appears to be a promising agent for the treatment of myeloma, and trials conducted for approval
by the FDA are under way.

Other Novel Agents

Several other agents, including 2-methoxyestradiol, neovastat, oblimersen, farnesyltransferase, and histone
deacetylase inhibitors, are being actively investigated. [10,112] Preliminary evidence suggests that arsenic trioxide has
clinical activity against myeloma, [116] and trials are under way to confirm this possibility and to determine optimal
dosing. Another thalidomide analogue, CC-4047, also has shown activity. [117]

Treatment of Complications

(Table 3) summarizes current management strategies for complications observed in patients with myeloma.
Important advances include the prevention and treatment of hypercalcemia and bony lesions with the monthly
administration of bisphosphonates in patients with myeloma bone disease. [118,119] Such treatment may be
complicated by albuminuria, renal dysfunction, and osteonecrosis of the jaw. Another recent advance is the use of
vertebroplasty or kyphoplasty to reduce pain and help restore vertebral height in patients with compression fractures.

Table 3. Treatment of Complications in Multiple Myeloma.

Future Directions

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Ongoing randomized trials promise to define further the roles of new agents, mini-allogeneic transplantation, and
maintenance therapy. There is a continuing search for active agents based on advances in understanding the biology of
myeloma. [112] Microarray-based pharmacogenomic analysis may usher in an era of therapy tailored to the individual
patient. [120]

Finally, two paths are being explored simultaneously, one to improve rates of complete response with the intense
use of available methods, which is aimed at finding a cure, and the other to exploit conventional and novel agents in
an effort to control myeloma and convert it into a chronic indolent disease. Success in either direction would be
momentous.

Supported in part by grants from the National Cancer Institute (CA62242, CA85818, CA93842, CA107476, and
CA100080), the Multiple Myeloma Research Foundation, and the Leukemia and Lymphoma Society.

Dr. Kyle reports having received consulting fees from NeoRx, Millennium, Aeterna, Celgene, and Novartis; and Dr.
Rajkumar consultation fees from Celgene and grants from Celgene and Millennium.

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multiple myeloma as a disease model. Mayo Clin Proc 2003;78:1098-109. [Context Link]

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