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Mieloma Multiple

Mieloma Multiple

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mieloma multiple
mieloma multiple

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02/01/2013

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 review article
 The 
 new england journal
of 
 medicine
 
n engl j med
351;18
 
www.nejm.org october
28, 2004
 
1860
 
drug therapy
 Multiple Myeloma
 Robert A. Kyle, M.D., and S. Vincent Rajkumar, M.D.
 
From the Division of Hematology and Inter-nal Medicine, Mayo Clinic, Rochester, Min-nesota. Address reprint requests to Dr. Kyleat the Division of Hematology and InternalMedicine, Mayo Clinic, 200 First St. S.W.,Rochester, MN 55905, or at kyle.robert@mayo.edu.N Engl J Med 2004;351:1860-73.
 Copyright © 2004 Massachusetts Medical Society.
 ultiple myeloma is a plasma-cell neoplasm that is charac-
 terized by skeletal destruction, renal failure, anemia, and hypercalcemia.
 
1
 Although myeloma remains incurable, recent advances in its treatment, in-cluding the use of thalidomide and new drugs such as bortezomib and CC-5013, arepromising.
 
2
 The most common symptoms on presentation are fatigue, bone pain, and recurrent in-fections.
 
3
 New diagnostic criteria require the presence of at least 10 percent plasmacells on examination of the bone marrow (or biopsy of a tissue with monoclonal plas-ma cells), monoclonal protein in the serum or urine, and evidence of end-organ dam-age.
 
4,5
 The end-organ damage that meets the criterion for the diagnosis consists of hy-percalcemia, renal insufficiency, anemia, or bone lesions (a group of findings referredto as CRAB).
 
4
 Occasional patients presenting without a detectable monoclonal proteinbut otherwise meeting these diagnostic criteria are considered to have nonsecretory myeloma. The serum free light-chain assay is useful for monitoring many patients witholigosecretory and nonsecretory myeloma. The differential diagnosis includes mono-clonal gammopathy of undetermined significance (MGUS), smoldering (asymptom-atic) multiple myeloma, primary amyloidosis, solitary plasmacytoma, low-grade lym-phoma, chronic lymphocytic leukemia, and metastatic carcinoma.
 
4
 The median length of survival after diagnosis is approximately three years. Recent advances have identified new prognostic markers, such as the complete deletion of chromosome 13 or its long arm, as detected by karyotyping; the t(4;14) or t(14;16)translocation; and increased density of bone marrow microvessels. These complement established markers of adverse outcomes, such as an increase in the plasma-cell–label-ing index, increased levels of serum beta
 
2
 -microglobulin, low levels of serum albumin,plasmablastic features in the bone marrow, and circulating plasma cells.
 
6
 evolution of mgus
 The first pathogenetic step in the development of myeloma is the emergence of a lim-ited number of clonal plasma cells, clinically known as MGUS.
 
7
 Patients with MGUSdo not have symptoms or evidence of end-organ damage, but they do have an annualrisk of 1 percent of progression to myeloma or a related malignant disease.
 
7
 Approx-imately 50 percent of patients have translocations that involve the immunoglobulinheavy-chain locus on chromosome 14q32 and one of five partner chromosomes,11q13 (
 CCND1
 ) (the most common), 4p16.3 (
 FGFR 
 -
 3
 and MMSET), 6p21 (
 CCND3
 ),
diagnosispathophysiology 
Copyright © 2004 Massachusetts Medical Society. All rights reserved.Downloaded from www.nejm.org on March 14, 2005 . This article is being provided free of charge for use in Colombia.
 
 
n engl j med
351;18
 
www.nejm.org october
28, 2004
 
drug therapy 
 
1861
 16q23 (c-
 maf 
 ), and 20q11 (
 mafB
 ).
 
8,9
 These andother cytogenetic changes (Fig. 1) are thought toplay an important role in the evolution of MGUS.
 progression to myeloma
 With progression of MGUS to myeloma, complexgenetic events occur in the neoplastic plasma cell(Fig. 1).
 
8
 Changes also occur in the bone marrow microenvironment, including the induction of angiogenesis, the suppression of cell-mediatedimmunity, and the development of paracrine sig-naling loops involving cytokines such as interleu-kin-6 and vascular endothelial growth factor.
 
10,11
 The resultant interactions of myeloma cells, bonemarrow stromal cells, and microvessels contributeto persistence of the tumor and its resistance todrugs.
 
9,10
 Understanding the cellular microenvi-ronment in myeloma has had a role in the develop-ment of drugs such as thalidomide and bortezomib,which are able to overcome chemotherapy-resis-tant disease.
 
10
 The development of bone lesions in myelomais thought to be related to an increase in the ex-pression by osteoblasts of the receptor activatorof nuclear factor-
 k
 B (NF-
 k
 B) ligand (RANKL) anda reduction in the level of its decoy receptor, os-teoprotegerin.
 
12
 The increase in the ratio of RANKLto osteoprotegerin results in the activation of os-teoclasts and bone resorption. Overexpression of RANKL is probably mediated in part by the releaseof macrophage inflammatory protein 1
 a
 by neo-plastic plasma cells.
 
13
 Improved understanding of myeloma-associated bone disease has led to the useof prophylactic bisphosphonate therapy.
 
9
 There is no evidence that early treatment of asymp-tomatic (smoldering) multiple myeloma is bene-ficial.
 
14,15
 The median time from diagnosis to theprogression to symptomatic disease is two to threeyears. Two recent studies suggest that thalidomidemay delay the time to progression.
 
16,17
 However,because some patients may remain progression-free for several years, therapy for asymptomatic my-eloma is not recommended, given the toxic effectsof thalidomide. An approach to the treatment of newly diagnosed myeloma is illustrated in Figure 2.
therapy 
 Figure 1.Mechanisms of Disease Progression in the Monoclonal Gammopathies.
 Percentages are the proportions of patients with the abnormality. Microenvironmental changes include increased bone resorption  medi-ated by increased production of receptor activator of nuclear factor-
 k
 B ligand, decreased levels of osteoprotegerin, and increased levels of macrophage inflammatory protein 1
 a
 ; the induction of angiogenesis; increased levels of interleukin-6 and vascular endothelial growth factor;and decreased immune surveillance.
Genomic instabilityMicroenvironmental changesin bone marrow
Translocationsat 14q32(50%)Deletion of chromosome 13(50%)Normal cellInfection?Inflammation?MyelomaMonoclonal gammopathyof undetermined significanceIncreased boneresorptionIncreasedangiogenesis
N-RAS, K-RAS 
(30%)p16 Methylation (40%)Secondary translocations?
Copyright © 2004 Massachusetts Medical Society. All rights reserved.Downloaded from www.nejm.org on March 14, 2005 . This article is being provided free of charge for use in Colombia.
 
 
n engl j med
351;18
 
www.nejm.org october
28
 
,
2004
 The 
 new england journal
of 
 medicine
 
1862
 When possible, patients should be encouraged toparticipate in clinical trials at the time of diagnosisand beyond.
induction therapy in patients eligiblefor autologous stem-cell transplantation
 Patients who are eligible for autologous stem-celltransplantation are first treated with a regimen that is not toxic to hematopoietic stem cells. The use of alkylating agents is best avoided, because they canprevent an adequate mobilization of stem cells.
 
18
 Many physicians use vincristine, doxorubicin, anddexamethasone for three to four months as induc-tion therapy.
 
19
 Despite an acceptable response rate,this therapy and similar intravenous regimens havedisadvantages, including the need for an indwellingcentral venous line and the risk of catheter-relat-ed infections, thrombotic events, and alopecia. Fur-thermore, the role of doxorubicin and vincristinein the regimen consisting of vincristine, doxorubi-cin, and dexamethasone is limited, because dexa-methasone alone contributes to most of the activi-ty (Table 1).An alternative choice for induction is the oralregimen of thalidomide plus dexamethasone. Ina recent trial, 50 patients with newly diagnosed my-eloma were treated with this combination.
 
28
 Tha-lidomide (at a dose of 200 mg per day) was givenwith dexamethasone (at a dose of 40 mg per day)on days 1 through 4, 9 through 12, and 17 through20 (odd cycles) and on days 1 through 4 (even cy-cles). Each cycle was 28 days long, and there wastypically no gap between the cycles unless time wasneeded for the resolution of toxic effects. The re-sponse rate in the patients in this trial was 64 per-cent, which is similar to that in previous trials withthe regimen of vincristine, doxorubicin, and dexa-methasone. No important problems were found inthe collection or engraftment of stem cells in thepatients after receiving this induction therapy.
 
28,34
 Deep-vein thrombosis was an unexpected adverseevent in 12 percent of the patients in this trial. In aseparate trial, the response rate with this regimenwas 72 percent, and the use of prophylactic antico-agulation with warfarin or low-molecular-weight heparin prevented the occurrence of deep-veinthrombosis.
 
17
 In a randomized trial comparing tha-lidomide plus dexamethasone with dexamethasonealone, the response rate with thalidomide plus dex-amethasone was significantly better (P=0.01).
 
35
 induction therapy in patients not eligiblefor transplantation
 Patients who are not eligible for transplantationbecause of age, poor physical condition, or coexist-ing conditions receive standard therapy with alkyl-ating agents.
 
36
 Although vincristine, doxorubicin,and dexamethasone, dexamethasone alone, or tha-lidomide plus dexamethasone can also be used asinitial therapy for these patients, the oral regimenof melphalan plus prednisone is preferable in thissetting to minimize toxic effects, unless there is aneed for a rapid response, such as in patients withlarge, painful lytic lesions or with worsening renal
 Figure 2.An Approach to the Treatment of Newly Diagnosed Multiple Myeloma.
 Induction therapy for patients eligible for transplantation is administeredin four cycles before stem cells are harvested. The term “plateau” indicatesa minimum of 12 months of therapy and the achievement of stable diseasefor at least 2 months. Asterisks denote investigational therapies.
Eligible fortransplantationStem-cell harvestAutologoustransplantationSecond autologoustransplantation*ormini–allogeneictransplantation*Melphalan plus prednisoneorthalidomide–dexamethasone*until plateau is reachedDexamethasoneorvincristine,doxorubicinand dexamethasoneorthalidomide–dexamethasone*Melphalan plus prednisoneorother alkylator-based therapyuntil plateau is reachedNot eligible fortransplantationNo treatment or corticosteroids* or thalidomide*
InductionTherapyConsolidationTherapyMaintenanceTherapy
Copyright © 2004 Massachusetts Medical Society. All rights reserved.Downloaded from www.nejm.org on March 14, 2005 . This article is being provided free of charge for use in Colombia.

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