Myeloma multiple disease

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Clinical Practice Guidelines in Oncology – v.1.2003 Continue Multiple Myeloma Version 1.2003

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  • Clinical Practice Guidelines in Oncology v.1.2003

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    MultipleMyeloma

    Version 1.2003

  • Guidelines IndexMultiple Myeloma TOC

    MS, ReferencesNCCN Practice Guidelinesin Oncology v.1.2003

    Version 1.2003, 11/05/03 2003 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

    NCCN Multiple Myeloma Panel Members

    Kenneth C. Anderson, MD/ChairDana-Farber Cancer Institute

    Melissa Alsina, MDH. Lee Moffitt Cancer Center & Research Instituteat the University of South Florida

    William Bensinger, MDFred Hutchinson Cancer Research Center/SeattleCancer Care Alliance

    J. Sybil Biermann, MDUniversity of Michigan ComprehensiveCancer Center

    Asher Chanan-Khan, MDRoswell Park Cancer Institute

    Benjamin Djulbegovic, MDH. Lee Moffitt Cancer Center & ResearchInstitute at the University of South Florida

    Sherif Farag, MD, PhDArthur G. James Cancer Hospital & Richard J.Solove Research Institute at The Ohio StateUniversity

    Ruby Meredith, MD, PhDUniversity of Alabama at BirminghamComprehensive Cancer Center

    Stephen J. Noga, MD, PhDThe Sidney Kimmel Comprehensive CancerCenter at Johns Hopkins

    Jeffrey Schriber, MDCity of Hope Cancer Center

    Dennis Shrieve, MDHuntsman Cancer Institute at theUniversity of Utah

    Mitchell R. Smith, MD, PhDFox Chase Cancer Center

    Keith Stockerl-Goldstein, MD, PhDStanford Hospital and Clinics

    Stefano Tarantolo, MDUNMC Eppley Cancer Center at theUniversity of Nebraska Medical Center

    Ann Traynor, MDRobert H. Lurie Comprehensive CancerCenter of Northwestern University

    Donna Weber, MDUniversity of Texas M. D. Anderson CancerCenter

    Joachim Yahalom, MDMemorial Sloan-Kettering Cancer Center

    Furhan Yunus, MDUniversity of Tennessee Health SciencesCenter/ St. Jude Childrens ResearchHospital

    *

    * Writing Committee member

    Multiple Myeloma

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    Table of Contents

    Multiple Myeloma:

    Waldenstrms Macroglobulinemia:

    NCCN Multiple Myeloma Panel Members

    Guidelines IndexPrint the Multiple Myeloma Guidelines

    Diagnostic Workup and Clinical Presentations (MYEL-1)

    Additional Treatment after Primary Treatment (MYEL-4)Primary Refractory Disease (MYEL-5)

    Osseous or Extraosseous Solitary Plasmacytoma: Primary Treatment (MYEL-2)Systemic Multiple Myeloma: Primary Treatment and Follow-up (MYEL-3)

    Primary Amyloidosis (AMYL-A)

    Workup and Primary Treatment (WALD-1)Surveillance and Follow-up (WALD-2)

    For help using thesedocuments, please click here

    ManuscriptReferences

    These guidelines are a statement of consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinicianseeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances todetermine any patient's care or treatment. The National Comprehensive Cancer Network makes no representations nor warranties of any kindwhatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way. These guidelines arecopyrighted by National Comprehensive Cancer Network. All rights reserved. These guidelines and the illustrations herein may not be reproduced inany form without the express written permission of NCCN. 2003.

    Multiple Myeloma

    Clinical Trials:

    Categories of Consensus:NCCNAll recommendations are Category2A unless otherwise specified.See

    Thebelieves that the best managementfor any cancer patient is in a clinicaltrial. Participation in clinical trials isespecially encouraged.

    NCCN

    To find clinical trials online at NCCNmember institutions, click here:nccn.org/clinical_trials/physician.html

    NCCN Categories of Consensus

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    Version 1.2003, 11/05/03 2003 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

    PrimaryTreatment(See MYEL-3)

    MYEL-1

    Note: All recommendations are category 2A unless otherwise indicated.

    Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

    H&P

    CBC, differential, platelets

    BUN/creatinine, electrolytes

    Calcium/albumin

    Quantitative immunoglobulins

    24h UPEP and immunofixation

    Skeletal survey

    Unilateral bone marrow aspirate +

    biopsy

    24-hour urine for Bence Jones

    quantitationBeta -microglobulin

    Labeling index

    LDH

    Cytogenetics

    Bone marrow flow cytometry

    SPEP and immunofixation

    2C-reactive protein

    Generally Useful Testsa

    a

    bc

    These tests may have prognostic significance in some patients..

    .

    Smoldering Multiple Myeloma (See MYEL-A)Durie-Salmon Staging (See MYEL-B)

    CLINICALPRESENTATION

    Systemic,smolderingor Stage Imyeloma

    b

    c

    Systemic, allother stagesof myelomac

    Solitaryplasmacytomac

    Osseous: PrimaryTreatment(See MYEL-2)

    Extraosseous:Primary Treatment(See MYEL-2)

    Useful Under Some Circumstances

    MRI for suspected cord compression

    MRI of spine for suspicion of solitary

    plasmacytoma of bone

    CT scan for evaluation of suspected

    extraosseous plasmacytoma

    (Avoid contrast)

    Tissue biopsy to diagnose a solitary

    osseous or extraosseous

    plasmacytoma

    Serum viscosity

    Bone marrow immunohistochemistry

    PET scan

    INITIAL DIAGNOSTIC WORKUP

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    Version 1.2003, 11/05/03 2003 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. MYEL-2

    SolitaryOsseous

    SolitaryExtraosseous

    Quantitative immuno-globulins + quantitation ofM protein after RTCBC, differential, plateletsBone survey annually orfor symptomsBone marrow biopsy asclinically indicatedParaprotein measurementevery 3-6 mo as clinicallyindicated

    RT ( 45 Gy) toinvolved field

    RT ( 45 Gy) toinvolved fieldand/or surgery

    Restagewithmyelomawork up

    Treat as indicatedfor systemicmyeloma (MYEL-3)

    Paraprotein measurementevery 3 mo for 4 cycles,then every 12 moCT or MRI every 6 mo for2 cycles, then as clinicallyindicated

    Primaryrefractorye

    orResponsefollowed byprogression

    CLINICALPRESENTATION

    PRIMARYTREATMENT

    FOLLOW-UP/SURVEILLANCEd

    dModified as clinically indicated.Primary refractory: Defined by less than 50% decrease in M protein in serumand/or new bone disease or hypercalcemia.

    e

    Note: All recommendations are category 2A unless otherwise indicated.

    Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

    Return to Multiple MyelomaTable of Contents

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  • Guidelines IndexMultiple Myeloma TOC

    MS, ReferencesNCCN Practice Guidelinesin Oncology v.1.2003

    Version 1.2003, 11/05/03 2003 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. MYEL-3

    Note: All recommendations are category 2A unless otherwise indicated.

    Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

    Systemic,smolderingor Stage Imyeloma

    b

    c

    Observe(category 1)

    Follow pathway forsystemic myeloma, below

    Progression to stage II orhigher diseaseh

    Systemic, allother stagesof myelomac

    Conventional dosechemotherapy ,bisphosphonates +adjunctive treatmentas indicated

    f

    g

    g

    Quantitative immuno-

    globulins + quantitation

    of M protein at least every

    3 mo

    CBC, differential, platelets

    BUN, creatinine, calcium

    Bone survey annually or

    for symptoms

    Bone marrow biopsy as

    clinically indicated

    Responsei

    Primaryrefractorydiseasee

    Stem-cell harvest,if candidate fortransplantation

    SeeAdditionalTreatment(MYEL-4)

    SeeAdditionalTreatment(MYEL-5)

    bc

    d

    fgh

    .

    Modified as clinically indicated.

    .

    .

    Disease progression: Defined by a sustained 25% rise in M protein in serum or urine or development of new sites oflytic disease or hypercalcemia.

    ePrimary refractory: Defined by less than 50% decrease in M protein in serum and/or new bone disease orhypercalcemia.

    Disease Response: Defined by a sustained 5 decline in M protein in serum or urine.

    i

    See Smoldering Multiple Myeloma (MYEL-A)Durie-Salmon Staging (MYEL-B)

    See Conventional chemotherapy (MYEL-C)See Adjunctive treatment (MYEL-D)

    .

    Return to Multiple MyelomaTable of Contents

    Multiple Myeloma

    CLINICALPRESENTATION

    PRIMARYTREATMENT

    FOLLOW-UP/SURVEILLANCEd

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    Version 1.2003, 11/05/03 2003 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. MYEL-4

    Quantitative

    immunoglobulins +

    quantitation of M

    protein at least

    every 3 mo

    CBC, differential,

    platelets

    BUN, creatinine,

    calcium

    Bone survey

    annually or for

    symptoms

    Bone marrow

    biopsy as clinically

    indicated

    Note: All recommendations are category 2A unless otherwise indicated.

    Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

    Systemicdisease:

    rimarytreatment

    Responseafter p

    Responseor stable

    i

    Responseor stable

    i

    Progressivediseaseh

    Progressivediseaseh

    ADDITIONAL TREATMENTFOLLOW-UP/SURVEILLANCE

    Post-transplantmaintenancetherapyin clinical trial

    Post-transplantmaintenancetherapyin clinical trial

    Salvage therapyon or off clinicaltrialorDonor lymphocyteinfusion

    Salvage therapyon or off clinicaltrialorAllogeneic stemcell transplant inclinical trial(category 3 forclinical trial vsconventional)orSecondautologoustransplant on oroff clinical trial

    j

    Progressivediseaseh

    Progressivediseaseh

    hDisease progression: Defined by a sustained 25% rise in M protein in serum or urine or development of new sites of lyticdisease or hypercalcemia.

    iDisease Response: Defined by a sustained 50% decline in M protein in serum or urine.Allogeneic transplantation may include nonmyeloablative (mini) alone or as tandem following autologous transplant or fullymyeloablative on a clinical trial.Single autologous transplantation: Category 1 evidence supports single stem cell transplant in clinically appropriatemyeloma patients. Tandem transplant should be performed only on a clinical trial.

    j

    k

    Continueconventionalchemotherapyto plateau

    Allogeneicstem cellsupportedtherapy inclinical trial

    j

    Autologousstem cellsupportedtherapy

    k

    or

    or

    Allogeneic:

    Autologous:

    Return to Multiple MyelomaTable of Contents

    Multiple Myeloma

    Observe/

    maintanence

    on or off

    clinical trial

    Progressivediseaseh

    Transplant

    candidate

    Non-transplant

    candidate

    Autologous

    BMT

    (category 1)

    Salvage therapy on

    or off clinical trial

    Progressivediseaseh

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    MS, ReferencesNCCN Practice Guidelinesin Oncology v.1.2003

    Version 1.2003, 11/05/03 2003 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

    ADDITIONAL TREATMENT

    MYEL-5

    Note: All recommendations are category 2A unless otherwise indicated.

    Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

    Systemic disease:Primary refractorydiseasee

    Autologous transplanton or off clinical trial(preferred)

    k

    or

    Salvage therapy on oroff clinical trial

    or

    Allogeneic transplanton a clinical trial

    j

    Return to Multiple MyelomaTable of Contents

    Multiple Myeloma

    e

    j

    k

    Primary refractory: Defined by less than 50% decrease in M protein in serum and/or new bone disease or hypercalcemia.Allogeneic transplantation may include nonmyeloablative (mini) alone or as tandem following autologous transplant or fullymyeloablative on a clinical trial.Single autologous transplantation: Category 1 evidence supports single stem cell transplant in clinically appropriatemyeloma patients. Tandem transplant should be performed only on a clinical trial.

  • Guidelines IndexMultiple Myeloma TOC

    MS, ReferencesNCCN Practice Guidelinesin Oncology v.1.2003

    Version 1.2003, 11/05/03 2003 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. MYEL-A

    Note: All recommendations are category 2A unless otherwise indicated.

    Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

    Criteria for diagnosis

    Monoclonal gammopathyM component:

    IgG > 35 g/L and < 50 g/L

    IgA > 20 g/L and < 30 g/L

    Bence Jones protein < 1.0 g/24 h

    Bone marrow infiltration with plasma cells

    > 10% but < 20%

    No anemia, renal failure, or hypercalcemia

    No bone marrow lesions on skeletal

    survey

    SMOLDERING MULTIPLE MYELOMA

    Return to ClinicalPresentation (MYEL-1)

    From: Durie BGM, Salmon SE: A clinical staging system for multiple myeloma., Vol 36, No 9, 1975: (CANCER 842-854, 1975 Copyright 1975) American Cancer Society.

    Reproduced with permission of John Wiley & Sons, Inc.

    Multiple Myeloma

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    MS, ReferencesNCCN Practice Guidelinesin Oncology v.1.2003

    Version 1.2003, 11/05/03 2003 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. MYEL-B

    Note: All recommendations are category 2A unless otherwise indicated.

    Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

    Table 1DURIE-SALMON STAGING SYSTEM FOR MULTIPLE MYELOMA

    Stage Criteria

    I All of the following:Hemoglobin > 10 g/dL

    Serum calcium level 12 mg/dL (normal)Normal bone or solitary plasmacytoma on x-rayLow M-component production rate:

    IgG < 5 g/dLIgA < 3 g/dLBence Jones protein < 4 g/24

    II Not fitting stage I or III

    III Any or more of the following:Hemoglobin < 8.5 g/dLSerum calcium level > 12 mg/dLMultiple lytic bone lesions on x-rayHigh M-component production rate:

    IgG > 7 g/dLIgA > 5 g/dLBence Jones protein > 12 g/24 h

    Myeloma cell mass(x 10 cells/m )

    < 0.6 (low)

    0.6-1.2 (intermediate)

    >1.2 (high)

    12 2

    Subclassification CriteriaA Normal renal function (serum creatinine level < 2.0 mg/dL)

    B Abnormal renal function (serum creatinine level 2.0 mg/dL)

    From: Durie BGM, Salmon SE: A clinical staging system for multiple myeloma., Vol 36, No 9, 1975: (CANCER 842-854, 1975 Copyright 1975) American Cancer Society.

    Reproduced with permission of John Wiley & Sons, Inc. Return to Clinical

    Presentation (MYEL-1)

    Multiple Myeloma

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    MS, ReferencesNCCN Practice Guidelinesin Oncology v.1.2003

    Version 1.2003, 11/05/03 2003 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. MYEL-C

    12Selected, but not inclusive of all regimens.Order does not imply preference.

    Note: All recommendations are category 2A unless otherwise indicated.

    Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

    Exposure to myelotoxic agents (including alkylating agents and nitrosoureas) should be

    limited to avoid compromising stem-cell reserve prior to stem-cell harvest in patients

    who may be candidates for transplant

    Primary conventional therapyMelphalan/prednisone (MP)Vincristine/doxorubicin/dexamethasone (VAD)DexamethasoneThalidomide/dexamethasone (Insufficient data to recommend treatment duration)

    Maintenance therapySteroids (category 1 for 50 mg prednisone every other day)Interferon

    SalvageRepeat primary conventional therapy (if relapse at > 6 mo)Cyclophosphamide-VADEtoposide/dexamethasone/cytarabine, cisplatin (EDAP)High-dose cyclophosphamideThalidomideBortezomib

    CONVENTIONAL CHEMOTHERAPY1,2

    Return to PrimaryTreatment (MYEL-2)

    Multiple Myeloma

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    MS, ReferencesNCCN Practice Guidelinesin Oncology v.1.2003

    Version 1.2003, 11/05/03 2003 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. MYEL-D

    Note: All recommendations are category 2A unless otherwise indicated.

    Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

    Bone Disease

    Hypercalcemia

    Hydration/furosemide, bisphosphonates, steroids and/or calcitoninHyperviscosity

    Plasmapheresis should be used as adjunctive therapy for symptomatic hyperviscosityAnemia

    Consider erythropoietin for anemic patientsInfection ( )

    Intravenous immunoglobulin therapy should be considered in the setting of recurrent life-threatening infection

    Consider pneumovax and influenza vaccine

    Consider PCP herpes and antifungal prophylaxis if high dose dexamethasone regimenRenal Dysfunction

    Maintain hydration to avoid renal failure

    Avoid use of NSAIDs

    Avoid IV contrast

    Plasmapheresis (category 2B)

    Not a contraindication to transplant

    BisphosphonatesAll patients with documented bone disease including osteopenia (category 1)Use of bisphosphonates in smoldering or stage I disease preferrably in the context of a clinical trial. These patients should have bone

    survey yearlyBone densitometry or metabolic studies should be reserved for clinical trialMonitor for renal dysfunction with chronic use of bisphosphonates

    Radiation TherapyLow-dose radiation therapy (1030 Gy) can be used as palliative treatment for uncontrolled pain, for impending pathologic fracture or

    impending cord compressionRadiation doses utilized should not preclude future administration of total-body irradiationLimited involved fields should be used to limit the impact of irradiation on stem-cell harvest or impact on potential future treatments

    Orthopedic consultation should be sought for impending or actual long-bone fractures or bony compression of spinal cord or vertebral

    column instability

    Consider vertebroplasty or kyphoplasty for symptomatic vertebral compression fractures

    (

    Monitor for renal dysfunction with chronic use of bisphosphonates

    )See NCCN Cancer and Treatment Related Anemia Guidelines

    See NCCN Fever and Neutropenia Guidelines

    ADJUNCTIVE TREATMENT

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    MS, ReferencesNCCN Practice Guidelinesin Oncology v.1.2003

    Version 1.2003, 11/05/03 2003 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

    Note: All recommendations are category 2A unless otherwise indicated.

    Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

    There are insufficient data to indicate the optimal

    treatment of amyloidosis and, therefore, all patients

    should be treated in the context of a clinical trial

    when possible.

    Therapeutic options include:

    Melphalan and prednisone

    Dexamethasone/VAD*

    Moderately high-dose melphalan therapy

    High-dose melphalan with stem-cell support

    * VAD therapy should be used with caution in patients who may have substantial cardiac disease.

    PRIMARY AMYLOIDOSIS

    AMYL-A

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    PRIMARY TREATMENT

    WALD-1

    Note: All recommendations are category 2A unless otherwise indicated.

    Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

    WORKUP

    Indications for treatment:

    Symptomatic

    hyperviscosity

    Anemia, pancytopenia

    Bulky adenopathy

    Symptomatic

    organomegaly

    Symptomatic

    cryoglobulinemia or

    neuropathy

    See Surveillanceand Follow-up(WALD-2)

    Waldenstrms Macroglobulinemia

    H&P

    CBC, differential, platelets

    BUN/creatinine, electrolytes

    Quantitative immunoglobulins

    SPEP/immunofixation

    Liver function tests

    Serum viscosity

    Unilateral bone marrow

    aspirate + biopsy

    Chest x-ray

    CT of chest/abdomen/pelvis

    Hepatitis serology

    Cryocrit

    a

    b

    Generally useful tests:

    Cold agglutinins

    Plasmapheresis forhyperviscosity

    andsymptomatic

    Alkylating agents

    or

    Nucleoside analogs2-CdAFludarabine

    or

    Clinical trials

    or

    Rituximab

    c,d

    a

    c

    d

    Most patients with serum viscosity of less than 4 cP will not havesymptoms of hyperviscosity.If cryocrit positive, then initial and follow-up sample should be measuredunder warm conditions.Preliminary data indicate significant response with minimal toxicity. Long-term results are unknown.For patients with M-protein > 5g/dL, use of rituximab alone is discouraged,reports of transient increase in M-protein have been noted with use ofrituximab alone.

    b

    Proposed Criteria for the Diagnosis of WM

    IgM monoclonal gammopathy of any concentration

    Bone marrow infiltration by small lymphocytes,

    plasmacytoid cells, and plasma cells

    Diffuse, interstitial, or nodular pattern of bone marrow

    infiltration

    Surface Ig+, CD5-, CD10-, CD19+, CD20+, CD23-

    immunophenotype

    Reprinted from Seminars In Oncology, Volume 30(2), Owen, RG, DevelopingDiagnostic Criteria in Waldenstrom's Macroglobulinemia, 196-200, Copyright(2003), with permission from Elsevier..

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    Version 1.2003, 11/05/03 2003 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. WALD-2

    Note: All recommendations are category 2A unless otherwise indicated.

    Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

    Every 2 cycles:CBCSPEPQuantitative

    immunoglobulins

    Every 3-6 mo:CT scan (if

    abnormal at

    presentation)

    If symptomatic then

    serum viscosity

    generally useful

    FOLLOW-UPSURVEILLANCE

    Initialtreatment:Alkylatingagents

    Initialtreatment:Nucleosideanalogs

    Progressivediseasee

    Alkylating agentsorNucleoside analogs(Fludarabine, category 1)orRituximab

    Nucleoside analogsorAlkylating agentsorRituximab

    Nucleoside analogs(Fludarabine, category 1)orRituximab

    Salvage in clinical

    trial including

    studies of stem-cell

    transplantation

    or

    Monoclonal

    antibodies:

    Rituximabor

    Thalidomide

    dexamethasone

    e

    fDisease progression: Defined by a sustained 25% rise in M protein in serum or urine, adenopathy or organomegaly.Disease Partial Response: Defined by at least 50% reduction in all measureable disease confirmed by a secondmeasurement at 4 weeks later.

    Waldenstrms Macroglobulinemia

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    Alkylating agentsorRituximab

    Initialtreatment:Rituximab

    ProgressivediseaseorResponse with

    relapse 6 mo

    e

    f

    Responsef

    with relapse > 6 mo

    Alkylating agents

    or

    Nucleoside analogs

    Rituximab

    or

    Alkylating agents

    or

    Nucleoside analogs

    ProgressivediseaseorResponse with

    relapse 6 mo

    e

    f

    Responsef

    with relapse > 6 mo

    ProgressivediseaseorResponse with

    relapse 6 mo

    e

    f

    Responsef

    with relapse > 6 mo

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    MS, ReferencesNCCN Practice Guidelinesin Oncology v.1.2003

    Version 1.2003, 11/05/03 2003 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

    Manuscript

    NCCN Categories of Consensus

    Multiple Myeloma

    Category 1

    Category 2A

    Category 2B

    Category 3

    All recommendations are category 2A unless otherwise noted.

    : There is uniform NCCN consensus, based on high-levelevidence, that the recommendation is appropriate.

    : There is uniform NCCN consensus, based on lower-level evidence including clinical experience, that therecommendation is appropriate.

    : There is nonuniform NCCN consensus (but no majordisagreement), based on lower-level evidence including clinicalexperience, that the recommendation is appropriate.

    : There is major NCCN disagreement that therecommendation is appropriate.

    Multiple myeloma will account for an estimated 14,600 (1.1%) ofnew cancer cases in the United States in the year 2003, including7800 cases in men (1.2%) and 6800 (1.0%) cases in women. It willalso be responsible for approximately 10,900 (2.0%) of cancerdeaths in 2003. The mean age of affected individuals is 62 years formen (75% older than age 70 years) and 61 years for women (79%older than age 70 years).Although myeloma cells are responsive to radiotherapy andchemotherapy, durable complete responses are rare. Chemotherapywith oral melphalan and prednisone (MP) produces response rates

    as high as 50% to 60%. However, prospective, randomized trials ofMP versus various combinations have failed to clearly show thatcombination chemotherapy improves survival. For maintenancetherapy, some studies have not confirmed a benefit from interferontherapy; however, other studies have reported that maintenancetherapy with steroids or recombinant interferon-alfa prolongs theresponse to conventional therapy in patients who have a near-complete response to chemotherapy or in those withimmunoglobulin A (IgA) or light-chain multiple myeloma. Studiesdemonstrate a benefit earlier in the disease course for stem celltransplant (SCT) as well as the activity of new drugs, such asthalidomide and bortezomib, even in patients with relapsed diseasepost-transplant. These statistics highlight the importance ofdeveloping new treatment strategies for this currently incurabledisease.

    The term conventional therapy is frequently used in theseguidelines; this term indicates the safety and efficacy of thetreatment have been validated and, as a result, the treatment isroutinely offered outside the context of a clinical trial. The termconventional therapy should not be confused with either

    chemotherapy or chemotherapy; thelatter typically refers to marrow-ablative doses. Stem celltransplant is also frequently used; this term refers to stem cellsharvested either from the bone marrow or peripheral blood and isfurther qualified to indicate whether the stem cells are autologous orallogeneic in origin. The term bone marrow transplant (BMT) mayhave been commonly used in the past, but, currently, peripheralstem cells are a more common source of stem cells.

    1

    2

    3,4

    5

    6

    7-9

    10,11

    conventional-dose high-dose

    MS-1

    Multiple Myeloma

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    Initial Diagnostic Workup

    Diagnostic Categories

    The initial diagnostic workup in all patients should include a historyand physical examination and the following baseline blood studies: acomplete blood count (CBC) with differential and platelet counts;blood urea nitrogen (BUN), serum creatinine, and serumelectrolytes; serum calcium and albumin; quantitativeimmunoglobulins; and serum protein electrophoresis (SPEP) andimmunofixation. Beta -microglobulin is also part of the initialdiagnostic workup. The level of beta -microglobulin reflects thetumor mass and has become a standard measure of the tumorburden. Other initial studies should include 24-hour urine for BenceJones quantitation, 24-hour urine protein electrophoresis (UPEP)and immunofixation, a skeletal survey, and unilateral bone marrowaspirate and biopsy. Most patients have serum proteins with orwithout associated urinary protein, but 20% of patients have urinaryproteins only. In the Mayo Clinic series of 1027 patients, 3% ofpatients have neither serum nor urine proteins and are truenonsecretors. Once the myeloma or monoclonal protein (M-protein) is quantitated, it is important to use the same test for serialstudies to ensure accurate relative quantitation.

    Generally useful tests are defined as those tests that should beperformed in most patients but may not be needed for some.Generally useful tests include: labeling index (popularized by theMayo Clinic to identify the fraction of the myeloma population that isproliferating); C-reactive protein, a surrogate marker forinterleukin-6 (which is a prime stimulator of myeloma cell growth);and lactic dehydrogenase (LDH), which can serve as a measure oftumor burden in lymphoma-like or plasmablastic myeloma.Cytogenetic tests may detect chromosomal abnormalities,

    particularly deletions, which may suggest a worse prognosis. Bonemarrow flow cytometry (which is used to quantify the number ofphenotypically abnormal plasma cells) may help confirm thediagnosis.

    Additional tests useful under some circumstances include magneticresonance imaging (MRI) for suspected spinal cord compression orsolitary plasmacytoma of bone, computerized tomographic (CT)scan (avoiding contrast) for evaluation of suspected extraduralextraosseous plasmacytomas, and serum viscosity if hyperviscosityis suspected. A tissue biopsy may also be necessary to confirm thepresence of plasmacytomas. Erythropoietin levels may also beobtained to help determine whether erythropoietin therapy isnecessary. Bone marrow immunohistochemistry may be useful insome cases to confirm presence of monoclonal plasma cells. Theuse of positron emission tomographic (PET) scanning may also behelpful to determine the extent of disease.

    The diagnostic criteria for myeloma have been previouslypublished and include excess monoclonal plasma cells and M-protein in most patients. Based on the results of the clinical andlaboratory evaluation previously discussed, patients are generallyclassified into four categories with prognostic significance:smoldering myeloma , Durie-Salmon stage I myeloma,plasmacytoma, or more advanced stages of systemic myeloma

    . However, patients with either smoldering myeloma orDurie-Salmon stage I myeloma are grouped together formanagement. A small subset of patients may be diagnosed with asolitary osseous or extraosseous plasmacytoma. Osseousplasmacytoma is defined as a plasmacytoma emanating from bone

    2

    2

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    13 14

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    19(MYEL-A)

    (MYEL-B)

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    without other evidence of disease. The diagnosis of osseousplasmacytoma requires a very thorough evaluation to rule out thepresence of systemic disease because many patients presumed tohave solitary plasmacytomas are found to have occult disease.

    For those patients with osseousplasmacytoma, primary radiation therapy (45 Gy or more) to theinvolved field is the initial treatment and is potentially curative.Follow-up and surveillance consist of quantitative immunoglobulinsand quantitation of M-protein every 3 to 6 months starting afterradiotherapy (similar to systemic myeloma) and as clinicallyindicated, a CBC with differential and platelets, a bone surveyannually or for symptoms, and a bone marrow biopsy to assesschanges in clinical status. Patients with primary refractory disease(defined by a less than 50% decrease in the M-protein in serumand/or new bone disease or hypercalcemia) should be reevaluatedfor myeloma, with systemic therapy as indicated.

    Solitary plasmacytomas derived from soft tissue are termedextraosseous and are treated initially with radiation therapy (45 Gyor more) to the involved field and/or surgery. Serum M-protein isfollowed in the same manner as for osseous plasmacytomas.However, CT scans may be repeated at 6-month intervals during thefirst year and thereafter as clinically indicated. Again, a stable orfalling paraprotein level is not an indication for further therapy.However, if the serum M-protein decreases by less than 50% and/ornew bone disease or hypercalcemia occurs, then the patient shouldbe re-evaluated for recurrent extraosseous plasmacytoma ormyeloma, with systemic therapy administered as indicated.

    Patients with smolderingmyeloma have an indolent course for many years without therapy.These patients have low concentrations of M-protein and bonemarrow infiltration with 10% to 20% of plasma cells; however, theydo not have anemia, renal failure, hypercalcemia, or bone lesions.Patients with Durie-Salmon stage I myeloma also have low amountsof M-protein without significant anemia, hypercalcemia, or bonedisease

    Patients with smoldering or stage I myeloma do not need primarytherapy (category 1) because they can do well for many months toyears before the disease progresses. These patients shouldinitially be observed. If their disease progresses to stage II or higher,then patients should be treated according to the guidelines foradvanced multiple myeloma. Disease progression is defined as asustained 25% or greater increase in M-protein in serum or urine,development of new sites of lytic disease, or hypercalcemia.

    Most patients who present withadvanced multiple myeloma (Durie-Salmon stage II and stage III)require primary therapy with conventional chemotherapyand bisphosphonates; 80% of these patients have bone disease andup to 33% have renal compromise. Complications such ashypercalcemia or hyperviscosity should be treated with adjunctivemeasures . Examples of conventional-dose primarytherapy include MP, dexamethasone, orvincristine/doxorubicin/dexamethasone (VAD).Thalidomide/dexamethasone is also an option based on phase IIdata showing a 72% response rate with 16% complete responses;however, data are insufficient to recommend treatment duration. AnMP regimen has been demonstrated to result in a 60% response

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    Primary Treatment

    Solitary Plasmacytoma:

    Indolent (Smoldering) or Stage I Myeloma:

    Advanced Multiple Myeloma:

    (MYEL-B)

    MYEL-C

    MYEL-D)

    .

    ( )

    (

    MS-3

    Multiple Myeloma

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    rate with a duration of 18 months and an overall survival of 24 to 36months. Response rates to primary combination chemotherapy andMP are equivalent, although the response to combination treatmentmay occur more rapidly. Stem cell toxins, such as nitrosoureas oralkylating agents, and pelvic irradiation may compromise stem cellreserve and, therefore, should be avoided in patients who arepotential candidates for autologous stem cell harvest and high-dosetherapy.

    Follow-up and surveillance for response consist of quantitativeimmunoglobulins and quantitation of M-protein with alternate cyclesof therapy and then at least every 3 months; CBC with differentialand platelets; BUN, serum creatinine, and serum calcium; bonesurvey annually or for symptoms; and bone marrow biopsy to assesschanges in clinical status. Treatment should be continued for, atmost, two cycles beyond maximal response; continued treatmentdoes not prolong the duration of the plateau phase.

    If a response occurs, several approaches for further managementbased on the age, characteristics, and preferences of the patientmay be used:

    Patients with disease that is responsive to or stabilizes duringprimary therapy with non-stem cell toxins may be either observed

    only or treated with maintenance therapy with steroids.5 Patientstreated with 50 mg prednisone every other day after achieving aresponse on a VAD-based regimen had a progression-free survivalof 14 months and an overall survival of 37 months when comparedto 5 and 26 months, respectively, for patients who did not undergomaintenance therapy. Maintenance therapy with interferon hasyielded inconsistent results.

    Alternatively, patients may be offered high-dose therapy andautologous SCT. Randomized clinical trials have established thetreatment efficacy of autologous SCT when compared with standardtherapy. A recent trial comparing high-dose therapy to standardtherapy showed an increase in the complete response rate and animprovement in overall survival (54 months in the high-dose groupcompared to 42 months for standard therapy). The benefit wasmore pronounced for higher risk patients. Similarly, a randomizedtrial from France assessed patients with responsive or stabledisease after primary therapy. This trial demonstrated thatautologous SCT is associated with statistically significant higherresponse rates as well as increased overall and event-free survivalwhen compared with the response of similar patients treated withconventional therapy. For this reason, this guidelinerecommendation is considered category 1, indicating uniform NCCNconsensus based on high-level evidence.

    Patients who are contemplating high-dose therapy if the diseaseprogresses may consider prophylactic harvest of stem cells at thetime of maximum response. All candidates for high-dosechemotherapy must have sufficient liver, renal, pulmonary, andcardiac function. High-dose chemotherapy can be used either aloneor together with total body irradiation (TBI) as ablative therapy.

    3

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    Follow-up Therapy and Surveillance

    ObservationMaintenance therapyAutologous stem cell supported therapyAllogeneic stem cell supported therapy in the context of a clinicaltrial

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    MS-4

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    Chemotherapy-only ablative regimens should be used in patientswho have received prior localized radiation therapy, which precludesthe safe administration of TBI. These regimens have recently beenshown to have equivalent efficacy and less toxicity than TBI. As thealgorithm notes, it is recommended that high-dose chemotherapy beoffered in the context of a clinical trial if possible.

    Allogeneic SCT may be considered in youngerpatients who have a histocompatible donor. Of note, allogeneic SCThas a higher rate of complications (ie, graft versus host disease) thanautologous transplantation. Indications for allogeneic SCT include:

    Patients whose disease responds to high-dose therapy andallogeneic SCT are candidates for maintenance therapy in clinicaltrials. In contrast, patients whose disease either does not respond toor relapses after allogeneic stem cell grafting may receive donorlymphocyte infusions in order to stimulate a beneficial graft-versus-myeloma effect. Salvage therapies may be offered on or offclinical trials. To decrease toxicity of the allotransplant while pre-serving the alloimmune graft-versus-myeloma effect,nonmyeloablative transplantation alone or preceded byautotransplantation is under evaluation in clinical trials.

    Studies have shown cell-selection methods candecrease myeloma cell contamination within autologous stem cellgrafts, but the use of these methods has not resulted in improvedoutcomes. If repeat SCTs are to be done on a clinical protocol,sufficient stem cells for both transplants should be collected at theoutset.

    Indications for an autologous SCT include:

    Patients whose disease responds to high-dose autologous stem celltherapy are candidates for post-transplantation maintenance therapyin clinical trials. Patients whose disease does not respond to orrelapses after autografting may be treated with salvage therapy (eitheron or off a clinical trial) or with allogeneic transplantation (category 3for clinical trial versus conventional therapy). Allogenic transplantationmay include nonmyeloablative (mini) alone or as tandem transplantafter autologous transplant or fully myeloablative in a clinical trial. Asecond autologous transplant (either on or off a clinical trial) is also arecommended option. Thalidomide has been shown to induceresponses in 30% of patients who relapse after SCT.

    Patients with progressive disease after primary therapy can betreated with salvage therapies, such as cyclophosphamide-VAD (C-VAD), etoposide/dexamethasone/cytarabine/cisplatin (EDAP), high-

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    29-31

    32-34

    35-37

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    10

    Allogeneic SCT:

    Autologous SCT:

    Patients with responsive or stable disease after primary therapy,when used in the context of a clinical trial

    Patients with responsive or stable disease after salvage therapy,when used in the context of a clinical trial

    Patients who experience progressive disease after a priorautologous SCT

    Patients with responsive or stable disease after primary therapy(category 1)

    Patients with responsive or stable disease after salvage therapy,when used in the context of a clinical trial.8,22,29-31,33,34,40-42

    Progressive Disease After Primary Therapy

    MS-5

    Multiple Myeloma

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    dose (non-marrow-ablative) cyclophosphamide, and thalidomide.In a recent trial of heavily pretreated patients, including high-dosetherapy, bortezomib induced remissions in 35% of patients; 28% ofthese responses were either complete or near complete. Somepatients who respond to salvage therapy are candidates for high-dose therapy and either allogeneic or autologous SCT. In thissetting, it is recommended that high-dose chemotherapy be offeredeither on or off a clinical trial.

    Important advances have been made in adjunctive treatment ofpatients with multiple myeloma .

    Bony manifestations of myeloma in the form of diffuse osteopeniaand/or osteolytic lesions develop in 85% of patients. Relatedcomplications are the major cause of limitations in quality of life andperformance status in patients with multiple myeloma. A large,double-blind, randomized trial has shown that monthly use ofintravenous pamidronate (a bisphosphonate) can decrease pain andbone-related complications, improve performance status, and,importantly, preserve quality of life in patients with Durie-Salmonstage III myeloma and at least one lytic lesion. Zoledronate ismore potent, can be administered more rapidly, and has equivalentbenefits. Based on published data and clinical experience, theguidelines recommend the use of bisphosphonates for all patientswith multiple myeloma who have bone disease, including osteopenia(category 1). In 10% to 20% of patients with earlier-stage diseasewho do not have bone disease, bisphosphonates may be consideredbut preferably in a clinical trial. An annual skeletal survey isrecommended for follow-up of bone disease. Bone densitometry or

    other metabolic studies should be reserved for clinical trials. Patientswho are chronic users of bisphosphonates should have their renalfunction monitored.

    Low-dose radiation therapy (10-30 Gy) is used for the palliativetreatment of uncontrolled pain, impending pathologic fracture, orimpending spinal cord compression. Limited involved fields shouldbe used to limit the effect of irradiation on stem cell harvest or itseffect on potential future treatments, and the radiation dosesadministered should not preclude future administration of TBI inpotential candidates for high-dose therapy and SCT. Orthopedicconsultation should be obtained for impending or actual fractures inweight-bearing bones, bony compression of the spinal cord, orvertebral column instability. Either vertebroplasty or kyphoplastyshould be considered for symptomatic vertebral compressionfractures.

    Hypercalcemia should be treated with hydration and furosemides,bisphosphonates, steroids, and/or calcitonin. Plasmapheresis shouldbe used as adjunctive therapy for symptomatic hyperviscosity (seeWaldenstrm's Macroglobulinemia, which is in a following section).Erythropoietin therapy should be considered for anemic patients,especially those with renal failure. Measuring endogenous erythropoi-etin levels may also be helpful in treatment planning. To preventinfection, intravenous immunoglobulin therapy should be consideredin the setting of recurrent, life-threatening infections; pneumococcaland influenza vaccine should also be considered; and

    pneumonia (PCP), herpes, and antifungal prophylaxis shouldalso be considered, if a high-dose dexamethasone regimen is used.Hydration should be maintained and nonsteroidal anti-inflammatory

    4 10,43

    11

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    46 47

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    Adjunctive Treatment

    Bone Disease

    Other Complications

    Pneumocystis

    carinii

    (MYEL-D)

    MS-6

    Multiple Myeloma

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    agents (NSAIDs) should be avoided to decrease the chances ofrenal dysfunction; however, renal dysfunction is not a contraindica-tion for transplant. The use of intravenous contrast media andNSAIDs should also be avoided in patients with renal impairment.Institutions differ in their use of plasmapheresis (category 2B) foradjunctive treatment of renal dysfunction.

    Primary amyloidosis is characterized by decreased numbers ofmonoclonal plasma cells in the bone marrow; however, the proteinproduced by these plasma cells has an affinity for visceral organs(such as kidney, heart, liver, and spleen) and causes related end-organ dysfunction.

    Treatment of primary amyloidosis should be in a clinical trialbecause data are insufficient to identify optimal treatment of theunderlying plasma cell disorder. These treatment options includeMP, dexamethasone/VAD, moderately high-dose melphalan, or high-dose melphalan therapy with autologous stem cell support. TheVAD regimen should be used with caution in patients who may havecardiac disease. In some patients, high-dose melphalan therapyfollowed by SCT can achieve responses, evidenced by reversal ofvisceral organ dysfunction.

    Waldenstrm's macroglobulinemia is characterized byhypersecretion of immunoglobulin M (IgM) in the serum; excesslymphoplasmacytoid cells in the bone marrow; and, in contrast tomultiple myeloma, the involvement of visceral organs, including theliver and spleen.

    The initial diagnostic workup includes a history and physicalexamination; CBC with differential and platelets; and BUN, serumcreatinine, and electrolytes. Quantitative immunoglobulins, SPEP,and immunofixation should be used to identify and quantify the M-protein (which is IgM) as is done in patients with multiple myeloma.IgM is a pentamer and a common cause of hyperviscosity.Therefore, evaluation for characteristic clinical signs and symptomsof serum viscosity should be done at the time of diagnosis.Waldenstrm's macroglobulinemia has been associated withunderlying hepatitis C; therefore, liver function tests and hepatitisC serology should be obtained as well.

    A unilateral bone marrow aspirate and biopsy will confirm excesslymphoplasmacytoid cells. CT scans of the chest, abdomen, andpelvis can assess organ involvement in patients who aresymptomatic and are done to follow patients with known visceralinvolvement. In patients with suggestive symptoms, useful testsinclude cold agglutinins or a cryocrit.

    Indications for the treatment of Waldenstrm's macroglobulinemiainclude symptomatic hyperviscosity; anemia; pancytopenia; bulkyadenopathy; and symptomatic organomegaly, cryoglobulinemia, orneuropathy. Primary treatment for patients who require systemictherapy includes alkylating agents or nucleoside analogs, such ascladribine (2-chlorodeoxyadenosine; 2-CdA), fludarabine, orrituximab. Cladribine can achieve complete responses when usedas both initial and salvage therapy. Steroids can be used alone orin combination with alkylating agents. Preliminary rituximab dataindicate significant response with minimal toxicity; however, long-

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    Workup

    Treatment

    Primary Amyloidosis

    Waldenstrm's Macroglobulinemia

    MS-7

    Multiple Myeloma

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    term results are not known. Treatment is typically continued untilmaximal response is achieved and then treatment is discontinued.

    Plasmapheresis is indicated for treatment of symptomatichyperviscosity, usually as a supplement to conventional systemictherapies. Plasmapheresis removes 80% of the IgM protein and istherefore quite effective in relieving the related signs and symptomsof hyperviscosity.

    Follow-up should include a CBC, quantitative immunoglobulins, andSPEP after every two treatment cycles. The same test should beused serially to ensure accurate quantitation of IgM protein. Serumviscosity is generally useful to assess symptomatic patients. If CTwas abnormal at presentation, it should be repeated at 3- to 6-monthintervals.

    Disease either responds or progresses after it is treated primarilywith alkylating agents. Patients whose disease responds should befollowed expectantly without any maintenance therapy. If thedisease progresses after 6 months or more, alkylating agents can berestarted, or nucleoside analogs or rituximab can be initiated;however, nucleoside analogs or rituximab should be used to treatearlier progressions. A similar treatment strategy is used for thosetreated primarily with nucleoside analogs (ie, when progression

    occurs after 6 months, the nucleoside analogs used earlier can berestarted, or an alkylating agent or rituximab can be started). Earlierprogressions should be treated with alkylating agents or rituximab.Similarly, patients treated initially with rituximab who relapse after 6months or more should be treated with rituximab, alkylating agents,or nucleoside analogs; this group of patients who experienceprogressive disease or early relapse should be treated withalkylating agents or nucleoside analogs.

    Patients whose disease progresses after second-line therapy arecandidates for salvage therapies (eg, SCT, monoclonal antibodiesincluding rituximab, or thalidomide with or without dexamethasone)in the context of clinical trials.

    Although multiple myeloma is sensitive to both chemotherapy andradiation therapy, it remains incurable at present. However,treatment algorithms (based on published data and clinicalexperience) can be developed to optimize therapy, which includesnot only therapy for the underlying disease but also supportivetherapy to enhance quality of life. Because myeloma is incurable,these guidelines prominently identify the clinical settings appropriatefor treatment of patients on clinical research protocols.

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    Follow-up and Surveillance

    Summary

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    Multiple Myeloma

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    39. Stewart AK, Vescio R, Schiller G et al. Purging of autologousperipheral-blood stem cells using CD34 selection does not improveoverall or progression-free survival after high-dose chemotherapyfor multiple myeloma: results of a multicenter randomized controlledtrial. J Clin Oncol 2001;19(17):3771-3779.40. Anderson KC. Who benefits from high dose therapy for multiplemyeloma? J Clin Oncol 1995;13:1291-1296.

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