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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)
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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
Guidelines IndexMultiple Myeloma TOC
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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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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.
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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)
.
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Multiple Myeloma
CLINICALPRESENTATION
PRIMARYTREATMENT
FOLLOW-UP/SURVEILLANCEd
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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:
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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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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
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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
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-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)
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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
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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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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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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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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
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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
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(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)
.
( )
(
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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.
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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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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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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
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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
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Adjunctive Treatment
Bone Disease
Other Complications
Pneumocystis
carinii
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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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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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Multiple Myeloma
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