Ovid_ Drug Therapy_ Multiple Myeloma

8/7/2019 Ovid_ Drug Therapy_ Multiple Myeloma

1/16

[Review Article]

Journals A-Z > New England Journal ... > 351(18) October 2004 > Drug Therapy: Multiple ...

The New England Journal of Medicine

Issue: Volume 351(18), 28 October 2004, pp 1860-1873

Copyright: Copyright 2004 Massachusetts Medical Society. A ll rights reserved.

Publication Type: [Review Article]

ISSN: 0028-4793

Accession: 00006024-200410280-00009

Drug Therapy: Multiple Myeloma

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

Author InformationFrom 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 [email protected].

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 atissue 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 o f 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-o rgan 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.

d: Drug Therapy: Multiple Myeloma. http://ovidsp.tx.ovid.com.ez69.periodicos.capes.gov.br/sp-3.4.0b/ovid...

16 23/04/2011 00:03


2/16

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 p rogression. [16,17] However, because some patients may remain

progression-free for several years, therapy fo r asymptomatic myeloma is not recommended, given the toxic effects of

thalidomide. An approach to the treatment of newly d iagnosed myeloma is illustrated inFigure 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 eligiblefor 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


16 23/04/2011 00:03


3/16

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, anddexamethasone. 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 o f 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.


16 23/04/2011 00:03


4/16

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 andprogression-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 def inite 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]


16 23/04/2011 00:03


5/16

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 d isease 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 o f 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 benef it from the use of interferon as maintenance therapy. [41]

A study by Berenson and colleagues [69] indicated that maintenance with predn isone 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 andmay 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


16 23/04/2011 00:03


6/16

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 Un iversity 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 ref ractory 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 forThalidomide Education and Prescribing Safety P rogram[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


16 23/04/2011 00:03


7/16

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 o f 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 tr ial 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, of ten painful, develops in approximately 30 percent of patients

and is more frequent in those who have prev iously 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 pro teasome 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]


16 23/04/2011 00:03


8/16

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 o f 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 ofvertebroplasty 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


16 23/04/2011 00:03


9/16

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, Ce lgene, and Novartis; and Dr.

Rajkumar consultation fees from Celgene and grants from Celgene and M illennium.

REFERENCES

1. Kyle RA, Rajkumar SV. Plasma cell disorders. In: Goldman L, Ausiello DA, eds. Cecil textbook of medicine. 22nd ed.

Philadelphia: W.B. Saunders, 2004:1184-95.[Context Link]

2. Anderson KC. Multiple myeloma: how far have we come? Mayo Clin Proc 2003;78:15-7. [Context Link]

3. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin

Proc 2003;78:21-33. [Context Link]

4. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple

myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 2003;121:749-57.

[Context Link]

5. Rajkumar SV, Dispenzieri A, Fonseca R, et al. Thalidomide for previously untreated indolent or smoldering multiple

myeloma. Leukemia 2001;15:1274-6. [Context Link]

6. Rajkumar SV, Greipp PR. Prognostic factors in multiple myeloma. Hematol Oncol Clin North Am 1999;13:1295-314.

Full Text [Context Link]

7. Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in monoclonal gammopathy of

undetermined significance. N Engl J Med 2002;346:564-9. Ovid Full Text [Context Link]

8. Kuehl WM, Bergsagel PL. Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer

2002;2:175-87. [Context Link]

9. Seidl S, Kaufmann H, Drach J. New insights into the pathophysiology of multiple myeloma. Lancet Oncol

2003;4:557-64. Full Text [Context Link]

10. Hideshima T, Anderson KC. Molecular mechanisms of novel therapeutic approaches for multiple myeloma. Nat Rev

Cancer 2002;2:927-37. [Context Link]

11. Rajkumar SV, Mesa RA, Fonseca R, et al. Bone marrow angiogenesis in 400 patients with monoclonal gammopathy of

undetermined significance, multiple myeloma, and primary amyloidosis. C lin Cancer Res 2002;8:2210-6. [Context Link]

12. Roodman GD. Role of the bone marrow microenvironment in multiple myeloma. J Bone Miner Res 2002;17:1921-5.

[Context Link]

13. Abe M, Hiura K, Wilde J, et al. Role for macrophage inflammatory protein (MIP)-1(alpha) and MIP-1(beta) in the

development of osteolytic lesions in multiple myeloma. Blood 2002;100:2195-202. [Context Link]

14. Hjorth M, Hellquist L, Holmberg E, Magnusson B, Rodjer S , Westin J. Initial versus deferred melphalan-prednisone

therapy for asymptomatic multiple myeloma stage I - a randomized study. Eur J Haematol 1993;50:95-102. [Context

Link]


16 23/04/2011 00:03


10/16

15. Grignani G, Gobbi PG, Formisano R, et al. A prognostic index for multiple myeloma. Br J Cancer 1996;73:1101-7.

[Context Link]

16. Rajkumar SV, Gertz MA, Lacy MQ, et al. Thalidomide as initial therapy for early-stage myeloma. Leukemia

2003;17:775-9. Ovid Full Text [Context Link]

17. Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously

untreated multiple myeloma. J Clin Oncol 2003;21:16-9. [Context Link]

18. Goldschmidt H, Hegenbart U, Wallmeier M, Hohaus S, Haas R. Factors influencing collection of peripheral blood

progenitor cells following high-dose cyclophosphamide and granulocyte colony-stimulating factor in patients with

multiple myeloma. Br J Haematol 1997;98:736-44. Buy Now [Context Link]

19. Alexanian R, Barlogie B, Tucker S. VAD-based regimens as primary treatment for multiple myeloma. Am J Hematol

1990;33:86-9. [Context Link]

20. Myeloma Trialists' Collaborative Group. Combination chemotherapy versus melphalan plus prednisone as treatment

for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. J Clin Oncol 1998;16:3832-42.[Context

Link]

21. Cavo M, Galieni P, Tassi C, Gobbi M, Tura S. M-2 protocol for melphalan-resistant and relapsing multiple myeloma.

Eur J Haematol 1988;40:168-73.

22. Alexanian R, Dimopoulos MA, Delasalle K, Barlogie B. Primary dexamethasone treatment of multiple myeloma.

Blood 1992;80:887-90.

23. Alexanian R, Barlogie B, Dixon D. High-dose glucocorticoid treatment of resistant myeloma. Ann Intern Med

1986;105:8-11.

24. Alexanian R, Barlogie B, Ventura G. Chemotherapy for resistant and relapsing multiple myeloma. Eur J Haematol

Suppl 1989;51:140-4.

25. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J

Med 1999;341:1565-71. [Erratum, N Engl J Med 2000;342:364.] [Context Link]

26. Kumar S, Gertz MA, Dispenzieri A, et al. Response rate, durability of response, and survival after thalidomide

therapy for relapsed multiple myeloma. Mayo Clin Proc 2003;78:34-9.[Context Link]

27. Juliusson G, Celsing F, Turesson I, Lenhoff S, Adriansson M, Malm C. Frequent good partial remissions from

thalidomide including best response ever in patients with advanced refractory and relapsed myeloma. Br J Haematol

2000;109:89-96. Buy Now

28. Rajkumar SV, Hayman S, Gertz MA, et al. Combination therapy with thalidomide plus dexamethasone for newly

diagnosed myeloma. J Clin Oncol 2002;20:4319-23. [Context Link]

29. Dimopoulos MA, Zervas K, Kouvatseas G, et al. Thalidomide and dexamethasone combination for refractory

multiple myeloma. Ann Oncol 2001;12:991-5. Buy Now [Context Link]

30. Palumbo A, Bertola A, Musto P, et al. Oral melphalan, prednisone and thalidomide for newly diagnosed myeloma.

Blood 2003;102:148a. abstract.

31. Garcia-Sanz R, Gonzalez-Fraile MI, Sierra M, Lopez C, Gonzalez M, San Miguel JF. The combination of thalidomide,

cyclophosphamide and dexamethasone (ThaCyDex) is feasible and can be an option for relapsed/refractory multiple

my-eloma. Hematol J 2002;3:43-8. [Context Link]

32. Richardson PG, Jagannath S, Schlossman R, et al. A multi-center, randomized, phase 2 study to evaluate the

efficacy and safety of 2 CDC-5013 dose regimens when used alone or in combination with dexa-methasone (Dex) for

the treatment of relapsed or refractory multiple myeloma (MM). Blood 2003;102:235a. abstract.[Context Link]


de 16 23/04/2011 00:03


11/16

33. Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N

Engl J Med 2003;348:2609-17. Ovid Full Text [Context Link]

34. Ghobrial IM, Dispenzieri A, Bundy KL, et al. Effect of thalidomide on stem cell collection and engraftment in

patients with multiple myeloma. Bone Marrow Transplant 2003;32:587-92. Buy Now [Context Link]

35. Rajkumar SV, Blood E , Vesole DH, Shepard R, Greipp PR. A randomised phase III trial of thalidomide plus

dexamethasone versus dexamethasone in newly diagnosed multiple myeloma (E1A00): a trial coordinated by the

Eastern Cooperative Oncology Group. Prog Proc Am Soc Clin Oncol 2004;23:558. abstract. [Context Link]

36. Rajkumar SV, Gertz MA, Kyle RA, Greipp PR. Current therapy for multiple myeloma. Mayo Clin Proc

2002;77:813-22. [Context Link]

37. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow

transplantation and chemotherapy in multiple myeloma. N Engl J Med 1996;335:91-7. Ovid Full Text

38. Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple

myeloma. N Engl J Med 2003;348:1875-83. Ovid Full Text

39. Blade J, Sureda A, Ribera JM, et al. High-dose therapy autotransplantation/intensification versus continued

conventional chemotherapy in multiple myeloma patients responding to initial chemotherapy: definitive results from

PETHEMA after a median follow-up of 66 months. Blood 2003;102:42a-43a. abstract. [Context Link]

40. Fermand J-P, Ravaud P, Katsahian S, et al. High dose therapy (HDT) and autologous blood stem cell (ABSC)

transplantation versus conventional treatment in multiple myeloma (MM): results of a randomized trial in 190 patients

55 to 65 years o f age. Blood 1999;94:Suppl 1:396a. abstract.

41. Barlogie B, Kyle R, Anderson K, et al. Comparable survival in multiple myeloma (MM) with high dose therapy (HDT)

employing MEL 140 mg/m(2)) + TBI 12 Gy autotransplants versus standard dose therapy with VBMCP and no benefit from

interferon (IFN) maintenance: results of intergroup trial S9321. Blood 2003;102:42a. abstract. [Context Link]

42. Fermand JP, Ravaud P, Chevret S, et al. High-dose therapy and autologous peripheral blood stem cell

transplantation in multiple myeloma: up-front or rescue treatment? Results of a multicenter sequential randomizedclinical trial. Blood 1998;92:3131-6.

43. Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem-cell transplantation for multiple

myeloma. N Engl J Med 2003;349:2495-502. [Erratum, N Engl J Med 2004;350:2628.] [Context Link]

44. Cavo M, Tosi P, Zamagni E, et al. The "Bologna 96" clinical trial of single vs. double autotransplants for previously

untreated multiple myeloma patients. Blood 2002;100:179a. abstract. [Context Link]

45. Fermand J-P, Alberti C, Marolleau J-P. Single versus tandem high dose therapy (HDT) supported with autologous

blood stem cell (ABSC) transplantation using unselected or CD34-enriched ABSC: results of a two by two designed

randomized trial in 230 young patients with multiple myeloma (MM). Hematol J 2003;4:Suppl 1:S59. abstract. [Context

Link]

46. Blade J, Vesole DH, Gertz M. Transplantation for multiple myeloma: who, when, how often? Patient selection and

goals. Blood 2003;102:3469-77. [Context Link]

47. Kumar A, Loughran T, Alsina M, Durie BG, Djulbegovic B. Management of multiple myeloma: a systematic review

and critical appraisal of published studies. Lancet Oncol 2003;4:293-304. Full Text [Context Link]

48. Moreau P, Facon T, Attal M, et al. Comparison of 200 mg/m(2)) melphalan and 8 Gy total body irradiation plus 140

mg/m(2)) melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly

diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myelome 9502 randomized trial. Blood

2002;99:731-5. [Context Link]

49. Palumbo A, Bringhen S, Petrucci MT, et al. A prospective randomized trial of intermediate dose melphalan (100

mg/m(2))) vs. oral melphalan/prednisone. Blood 2003;102:984a. abstract. [Context Link]


e 16 23/04/2011 00:03


12/16

50. Rajkumar SV, Fonseca R, Lacy MQ, et al. Autologous stem cell transplantation for relapsed and primary refractory

myeloma. Bone Marrow Transplant 1999;23:1267-72. [Context Link]

51. Blade J, Esteve J. Treatment approaches for relapsing and refractory multiple my-eloma. Acta Oncol

2000;39:843-7. [Context Link]

52. Facon T, Mary JY, Harousseau JL, et al. Front-line or rescue autologous bone marrow transplantation (ABMT)

following a first course of h igh dose melphalan (HDM) in multiple myeloma (MM): preliminary results of a prospective

randomized trial (CIAM protocol). Blood 1996;88:Suppl 1:685a. abstract. [Context Link]

53. Barlogie B, Jagannath S, Vesole DH, et al. Superiority of tandem autologous transplantation over standard therapy

for previously untreated multiple myeloma. Blood 1997;89:789-93. [Context Link]

54. Barlogie B, Jagannath S, Desikan KR, et al. Total therapy with tandem transplants for newly diagnosed multiple

myeloma. Blood 1999;93:55-65. [Context Link]

55. Goldschmidt H. Single vs. tandem autologous transplantation in multiple myeloma: the GMMG exper ience. Hematol

J 2003;4:Suppl 1:S61. abstract. [Context Link]

56. Sirohi B, Powles R, Singhal S, et al. High-dose melphalan and second autografts for myeloma relapsing after one

autograft: results equivalent to tandem autotransplantation. Blood 2001;98:402a. abstract. [Context Link]

57. Bensinger W, Giralt S, Ho lmberg L, et al. 166H0-DOTMP and high-dose melphalan before autologous peripheral

blood stem cell transplantation in patients with multiple myeloma. Hematol J 2003;4:Suppl 1:S215-S216. abstract.

[Context Link]

58. Dispenzieri A, Wiseman GA, Lacy MQ, et al. A phase II study of high dose 153-samarium EDTMP (153-Sm EDTMP) and

melphalan for peripheral stem cell transplantation (PBSCT) in multiple myeloma (MM). Blood 2003;102:982a. abstract.

[Context Link]

59. Stewart AK, Vescio R, Schiller G, et al. Purging of autologous peripheral-blood stem cells using CD34 selection does

not improve overall or progression-free survival after high-dose chemotherapy for multiple myeloma: results of a

multicenter randomized controlled trial. J Clin Oncol 2001;19:3771-9. [Context Link]

60. Barbui AM, Galli M, Dotti G, et al. Negative selection of peripheral blood stem cells to support a tandem autologous

transplantation programme in multiple myeloma. Br J Haematol 2002;116:202-10. Buy Now [Context Link]

61. Mehta J, Singhal S. Graft-versus-myeloma. Bone Marrow Transplant 1998;22:835-43. [Context Link]

62. Gahrton G, Svensson H, Cavo M, et al. Progress in allogeneic bone marrow and peripheral blood stem cell

transplantation for multiple myeloma: a comparison between transplants performed 1983-93 and 1994-98 at European

Group for Blood and Marrow Transplantation centres. Br J Haematol 2001;113:209-16. Buy Now [Context Link]

63. Lokhorst HM, Segeren CM, Verdonck LF, et al. Partially T-cell-depleted allogeneic stem-cell transplantation for

first-line treatment of multiple myeloma: a prospective evaluation of patients treated in the phase III study HOVON 24

MM. J Clin Oncol 2003;21:1728-33. [Context Link]

64. Einsele H, Schafer HJ, Hebart H, et al. Follow-up of patients with progressive multiple myeloma undergoing

allografts after reduced-intensity conditioning. Br J Haematol 2003;121:411-8. Buy Now [Context Link]

65. Maloney DG, Sahebi F, Stockerl-Goldstein KE, et al. Combining an allogeneic graft-vs-myeloma effect with

high-dose autologous stem cell rescue in the treatment of multiple myeloma. Blood 2001;98:434a-435a. abstract.

[Context Link]

66. Maloney DG, Molina AJ, Sahebi F, et al. A llografting with nonmyeloablative conditioning following cytoreductive

autografts for the treatment of patients with multiple myeloma. Blood 2003;102:3447-54. [Context Link]

67. Moreau P, Garban F, Facon T, et al. P reliminary results of the IFM9903 and IFM9904 protocols comparing autologous

followed by miniallogeneic transplantation and double autologous transplant in high-risk de novo multiple myeloma.

Blood 2003;102:43a. abstract. [Context Link]


de 16 23/04/2011 00:03


13/16

68. Myeloma Trialists' Collaborative Group. Interferon as therapy for multiple myeloma: an individual patient data

overview of 24 randomized trials and 4012 patients. Br J Haematol 2001;113:1020-34. Buy Now [Context Link]

69. Berenson JR, Crowley JJ, Grogan TM, et al. Maintenance therapy with alternate-day prednisone improves survival

in multiple myeloma patients. Blood 2002;99:3163-8. [Context Link]

70. Gertz MA, Lacy MQ, Inwards DJ, et al. Early harvest and late transplantation as an effective therapeutic strategy in

multiple myeloma. Bone Marrow Transplant 1999;23:221-6. [Context Link]

71. Hussein MA, Wood L, Hsi E, et al. A phase II trial of pegylated liposomal doxorubicin, vincristine, and reduced-dose

dexamethasone combination therapy in newly diagnosed multiple myeloma patients. Cancer 2002;95:2160-8. [Context

Link]

72. Gertz MA, Garton JP, Greipp PR, Witzig TE, Kyle RA. A phase II study of high-dose methylprednisolone in refactory

or relapsed multiple myeloma. Leukemia 1995;9:2115-8. [Context Link]

73. Lenz W. Thalidomide and congenital abnormalities. Lancet 1962;1:45. [Context Link]

74. Rajkumar SV, Mesa RA, Tefferi A. A review of angiogenesis and anti-angiogenic therapy in hematologic

malignancies. J Hematother Stem Cell Res 2002;11:33-47. [Context Link]

75. Grabstald H, Golbey R. C linical experiences with thalidomide in patients with cancer. Clin Pharmacol Ther

1965;40:298-302. [Context Link]

76. Olson KB, Hall TC, Horton J, Khung CL, Hosley HF. Thalidomide (N-phthaloylglutamimide) in the treatment of

advanced cancer. Clin Pharmacol Ther 1965;6:292-7. [Context Link]

77. Barlogie B, Desikan R, Eddlemon P, et al. Extended survival in advanced and refractory multiple myeloma after

single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients. Blood 2001;98:492-4.

[Context Link]

78. Rajkumar SV, Fonseca R, Dispenzieri A, et al. Thalidomide in the treatment of relapsed multiple myeloma. MayoClin Proc 2000;75:897-901. [Context Link]

79. Dimopoulos MA, Anagnostopoulos A, Weber D. Treatment of plasma cell dyscrasias with thalidomide and its

derivatives. J Clin Oncol 2003;21:4444-54. [Context Link]

80. Blade J, Perales M, Rosinol L, et al. Thalidomide in multiple myeloma: lack of response of soft-tissue

plasmacytomas. Br J Haematol 2001;113:422-4. [Context Link]

81. Weber DM, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide with dexamethasone for resistant multiple

myeloma. Blood 2000;96:167a. abstract. [Context Link]

82. Palumbo A, Giaccone L, Bertola A, et al. Low-dose thalidomide plus dexamethasone is an effective salvage therapy

for advanced myeloma. Haematologica 2001;86:399-403. Full Text [Context Link]

83. Anagnostopoulos A, Weber D, Rankin K, Delasalle K, Alexanian R. Thalidomide and dexamethasone for resistant

multiple myeloma. Br J Haematol 2003;121:768-71. Buy Now [Context Link]

84. Srkalovic G, Elson P, Trebisky B, Karam MA, Hussein MA. Use of melphalan, thalidomide, and dexamethasone in

treatment of refractory and relapsed multiple myeloma. Med Oncol 2002;19:219-26.[Context Link]

85. Ghobrial IM, Rajkumar SV. Management of thalidomide toxicity. J Support Oncol 2003;1:194-205. [Context Link]

86. Osman K, Comenzo R, Rajkumar SV. Deep venous thrombosis and thalidomide therapy for multiple myeloma. N EnglJ Med 2001;344:1951-2. Ovid Full Text [Context Link]

87. Zangari M, Anaissie E, Barlogie B, et al. Increased risk of deep-vein thrombosis in patients with multiple myeloma

receiving thalidomide and chemotherapy. Blood 2001;98:1614-5.[Context Link]


de 16 23/04/2011 00:03


14/16

88. Zangari M, Siegel E, Barlogie B, et al. Thrombogenic activity of doxorubicin in myeloma patients receiving

thalidomide: implications for therapy. Blood 2002;100:1168-71. [Context Link]

89. Zeldis JB, Williams BA, Thomas SD, Elsayed ME. S.T.E.P.S. : a comprehensive program for controlling and

monitoring access to thalidomide. Clin Ther 1999;21:319-30. Full Text [Context Link]

90. Eriksson T, Bjorkman S, Hoglund P. Clinical pharmacology of thalidomide. Eur J Clin Pharmacol 2001;57:365-76.

[Context Link]

91. Bauer KS, Dixon SC, Figg WD. Inh ibition of angiogenesis by thalidomide requires metabolic activation, which is

species-dependent. Biochem Pharmacol 1998;55:1827-34. Full Text [Context Link]

92. Hideshima T, Richardson P, Chauhan D, et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis,

and overcomes drug resistance in human multiple myeloma cells. Cancer Res 2001;61:3071-6. [Context Link]

93. Adams J, Palombella VJ, Sausville EA, et al. Proteasome inhibitors: a novel class of potent and effective antitumor

agents. Cancer Res 1999;59:2615-22. [Context Link]

94. Mitsiades N, Mitsiades CS, Poulaki V, et al. Molecular sequelae of proteasome inhibition in human multiple myeloma

cells. Proc Natl Acad Sci U S A 2002;99:14374-9. Full Text [Context Link]

95. Mitsiades N, Mitsiades CS, Richardson PG, et al. The proteasome inhibitor PS-341 potentiates sensitivity of multiple

myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 2003;101:2377-80. [Context

Link]

96. LeBlanc R, Catley LP, Hideshima T, et al. Proteasome inhibitor PS-341 inhibits human myeloma cell growth in vivo

and prolongs survival in a murine model. Cancer Res 2002;62:4996-5000. [Context Link]

97. Orlowski RZ, Stinchcombe TE, Mitchell BS, e t al. Phase I trial of the proteasome inhibitor PS-341 in patients with

refractory hematologic malignancies. J Clin Oncol 2002;20:4420-7. [Context Link]

98. Blade J, Samson D, Reece D, et al. Criteria for evaluating disease response and progression in patients with

multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Br J Haematol

1998;102:1115-23. Buy Now [Context Link]

99. Lee S, Richardson PG, Barlogie B, et al. Quality-of-life (QOL) and clinical benefit assessment in patients with

relapsed and refractory multiple myeloma (MM) treated with bortezomib. Prog Proc Am Soc Clin Oncol 2003;22:582.

abstract. [Context Link]

100. Richardson PGG, Barlogie B, Berenson JR, et al. Prognostic factors associated with response in patients with

relapsed and refractory multiple myeloma (MM) treated with bortezomib. Prog Proc Am Soc Clin Oncol 2003;22:581.


101. Berenson JR, Jagannath S, Barlogie B, et al. Experience with long-term therapy using the pro teasome inhibitor,

bortezomib, in advanced multiple myeloma (MM). Prog Proc Am Soc Clin Oncol 2003;22:581. abstract.[Context Link]

102. Richardson P, Sonneveld P, Schuster MW, et al. Bortezomib vs. dexamethasone in relapsed multiple myeloma: a

phase 3 randomized study. Prog Proc Am Soc C lin Oncol 2004;23:558. abstract.[Context Link]

103. Jagannath S, Richardson P, Barlogie B, et al. SUMMIT/CREST Investigators. Phase II trials of bortezomib in

combination with dexamethasone in multiple myeloma (MM): assessment of additional benefits to combination in

patients with sub-optimal responses to bortezomib alone. Prog Proc Am Soc Clin Oncol 2003;22:582. abstract. [Context

Link]

104. Yang HH, Vescio RA, Adams J, Schenkein D, Berenson JR. A phase I/II study of combination treatment with

bortezomib and melphalan (Vc+M) in patients with relapsed or re fractory multiple myeloma (MM). Prog Proc Am SocClin Oncol 2003;22:582. abstract. [Context Link]


de 16 23/04/2011 00:03


15/16

Select All ExportSelectedtoPowerPointExportSelectedtoPowerPointExportSelectedtoPowerPointExportSelectedtoPowerPoint

105. Orlowski RZ, Voorhees PM, Garcia R, et al. Phase I study of the p roteasome inhibitor bortezomib and pegylated

liposomal doxorubicin in patients with refractory hematologic malignancies. Prog Proc Am Soc Clin Oncol 2003;22:200.


106. Richardson P. Proteasome inhibitors in hematologic malignancies. Cancer Treat Rev 2003;29:Suppl 1:33-9.

[Context Link]

107. Almond JB, Cohen GM. The proteasome: a novel target for cancer chemotherapy. Leukemia 2002;16:433-43.

[Context Link]

108. Hideshima T, Mitsiades C, Akiyama M, et al. Mo lecular mechanisms mediating antimyeloma activity of pro teasome

inhibitor PS-341. Blood 2003;101:1530-4. [Context Link]

109. Palombella VJ, Rando OJ, Goldberg AL, Maniatis T. The ubiquitin-proteasome pathway is required for processing

the NF-(kappa)B1 precursor protein and the activation of NF-(kappa)B. Cell 1994;78:773-85. Full Text [Context Link]

110. Hideshima T, Chauhan D, Richardson P, et al. NF-(kappa)B as a therapeutic target in multiple myeloma. J Biol

Chem 2002;277:16639-47. [Context Link]

111. Mitsiades N, Mitsiades CS, Poulaki V, e t al. Apoptotic signaling induced by immunomodulatory thalidomide analogs

in human multiple myeloma cells: therapeutic implications. Blood 2002;99:4525-30. [Context Link]

112. Hideshima T, Chauhan D, Podar K, Schlossman RL, Richardson P, Anderson KC. Novel therapies targeting the

myeloma cell and its bone marrow microenvironment. Semin Oncol 2001;28:607-12. Full Text [Context Link]

113. Dredge K, Marriott JB, Macdonald CD, et al. Novel thalidomide analogues display anti-angiogenic activity

independently of immunomodulatory effects. Br J Cancer 2002;87:1166-72.[Context Link]

114. Zangari M, Tricot G, Zeldis J, Eddlemon P, Saghafifar F, Barlogie B. Results of phase I study of CC-5013 for the

treatment of multiple myeloma (MM) patients who relapse after high dose chemotherapy (HDCT). Blood 2001;98:775a.


115. Richardson PG, Schlossman RL, Weller E, et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is

well tolerated in patients with relapsed multiple myeloma. Blood 2002;100:3063-7. [Context Link]

116. Munshi NC. Arsenic trioxide: an emerging therapy for multiple myeloma. Oncologist 2001;6:Suppl 2:17-21.

[Context Link]

117. Streetly M, Jones RW, Knight R, et al. An update of the use and outcomes of the new immunomodulatory agent

CC-4047 (actimid) in patients with relapsed/refractory myeloma. Blood 2003;102:236a. abstract. [Context Link]

118. Berenson JR, Lichtenstein A, Porter L, et al. Efficacy of pamidronate in reducing skeletal events in patients with

advanced multiple myeloma. N Engl J Med 1996;334:488-93. Ovid Full Text [Context Link]

119. Berenson JR, Rosen LS, Howell A, e t al. Zoledronic acid reduces skeletal-related events in patients with

osteolytic metastases. Cancer 2001;91:1191-200. [Erratum, Cancer 2001;91:1956.] [Context Link]

120. Shaughnessy J Jr. Primer on medical genomics. IX. Scientific and clinical applications of DNA microarrays -

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

IMAGE GALLERY


de 16 23/04/2011 00:03


16/16

Figure 1

Figure 2

Table 1

Table 2

Figure 3 Table 3Back to Top

Copyright (c) 2000-2011 Ovid Technologies, Inc.

Terms of Use Support & Train ing About Us Contact Us

Version: Ov idSP_UI03.04.00.105, SourceID 54178


Ovid_ Drug Therapy_ Multiple Myeloma

Documents

Transcript of Ovid_ Drug Therapy_ Multiple Myeloma