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Evaluating Paraproteinemia
Jeffrey Wolf, MD, Director Jeffrey Wolf, MD, Director Thomas Martin, MD, Associate DirectorThomas Martin, MD, Associate Director
Myeloma InstituteMyeloma InstituteUniversity of California, San FranciscoUniversity of California, San Francisco
The Paraprotein
An abnormal immunoglobulin or part of an Ig An abnormal immunoglobulin or part of an Ig (light chain) in the blood or urine(light chain) in the blood or urineTypically produced by a clonal population of Typically produced by a clonal population of BB--cell derived plasma cellscell derived plasma cellsElderly > Young Elderly > Young African Americans > CaucasiansAfrican Americans > CaucasiansCommonCommon
Age > 50 yrs, 3.2% have a paraproteinAge > 50 yrs, 3.2% have a paraproteinAge > 70 yrs, 5.3% with paraproteinAge > 70 yrs, 5.3% with paraprotein
Not always malignancy associatedNot always malignancy associated
Paraprotein Structure
Heavy ChainsHeavy Chains
IgG >IgA>IgG >IgA>
IgM> IgDIgM> IgD
Light ChainsLight Chains
KappaKappa
LambdaLambda
Conditions Associated with PPNonNon--MalignantMalignant
AutoAuto--immune d/oimmune d/o’’ssSLESLERARAHashimotoHashimoto’’s s thyroiditisthyroiditis
Cutaneous diseaseCutaneous diseasePyoderma gangrenosumPyoderma gangrenosumLiver diseaseLiver disease
CirrhosisCirrhosisHepatitisHepatitis
Infectious diseaseInfectious diseaseMycobacteriumMycobacteriumBacterial endocarditisBacterial endocarditis
PrePre--malignantmalignantMGUSMGUS
MalignantMalignantSolitary PlasmacytomaSolitary PlasmacytomaMyelomaMyelomaPOEMS SyndromePOEMS SyndromePlasma cell leukemiaPlasma cell leukemiaAmyloidosisAmyloidosisChronic lymphocytic Chronic lymphocytic leukemialeukemiaWaldenstrom Waldenstrom MacrogobulinemiaMacrogobulinemiaNonNon--Hodgkin LymphomaHodgkin Lymphoma
What problems can the protein cause?
NeuropathyNeuropathyNephropathy (esp. light chains)Nephropathy (esp. light chains)CytopeniasCytopenias
ITPITPAIHAAIHA
Cold AgglutininsCold AgglutininsCryoglobulinsCryoglobulins
When to think about testing for a When to think about testing for a ParaproteinParaprotein
Malaise and fatigueMalaise and fatigueBone disease (persistent pain, osteopenia or lytic lesions)Bone disease (persistent pain, osteopenia or lytic lesions)Impaired renal functionImpaired renal functionNormochromic normocytic anaemia; pancytopeniaNormochromic normocytic anaemia; pancytopeniaHypercalcaemiaHypercalcaemiaRecurrent bacterial infectionsRecurrent bacterial infectionsHyperviscosityHyperviscosityNephrotic syndrome, cardiac failure, malabsorptionNephrotic syndrome, cardiac failure, malabsorptionPeripheral neuropathies, carpal tunnel syndromePeripheral neuropathies, carpal tunnel syndromeIncidental persistent elevated ESRIncidental persistent elevated ESRElevated total protein level in serumElevated total protein level in serum
Most Commonly Found as a Laboratory Diagnosis
Typically found when routine testing Typically found when routine testing shows an elevated serum total proteinshows an elevated serum total proteinFurther testing to evaluate PPFurther testing to evaluate PP
Serum protein electrophoresisSerum protein electrophoresisSerum immunofixation Serum immunofixation electrophoresiselectrophoresisSerum Serum freefree light chain (freelite)light chain (freelite)Quantitative immunoglobulinsQuantitative immunoglobulins
ParaproteinEvaluationSPEPSPEP
QuantitativeQuantitativeBest test to quantity M proteinBest test to quantity M protein
UPEPUPEPQuantitativeQuantitativeRequires 24 hr urine collectionRequires 24 hr urine collection
Immunoglobulin levelsImmunoglobulin levelsIgA, IgG, IgM, IgDIgA, IgG, IgM, IgDAbnormal + normal proteinAbnormal + normal protein
ParaprotienEvaluation
IFEIFENot QuantitativeNot QuantitativeIdentifies heavy Identifies heavy chain (IgG, IgA, IgM ) chain (IgG, IgA, IgM ) and light chain (and light chain (λ, κλ, κprotein) type protein) type Most Sensitive test to Most Sensitive test to evaluate for an Mevaluate for an M--proteinprotein
Paraprotein Evaluation- SFLCSerum Free Light ChainSerum Free Light Chain
Assay detects only free LCAssay detects only free LC(cannot bind bound LC)(cannot bind bound LC)QuantitativeQuantitativeShould be correlated toShould be correlated to24 hour urine and UPEP24 hour urine and UPEP
Excellent for following disease progression in Excellent for following disease progression in MGUS, disease response in LC myeloma, and MGUS, disease response in LC myeloma, and even disease in myeloma after SPEP normaleven disease in myeloma after SPEP normal(stringent CR)(stringent CR)Is used for prognosis in MGUS (later)Is used for prognosis in MGUS (later)
Plasma Cell Disorders
MGUSMGUSSolitary PlasmacytomaSolitary PlasmacytomaMultiple MyelomaMultiple MyelomaWaldenstrom Waldenstrom MacroglobulinemiaMacroglobulinemiaAmyloidosisAmyloidosisPOEMS SyndromePOEMS SyndromeLymphoplasmacytic Lymphoplasmacytic lymphomalymphoma
WM
POEMS
AmyloidMM
MGUS
LL
SP
Mayo Clinic
ExperienceExperience
1684 with PP1684 with PP
Kyle and Kumar, Kyle and Kumar, British Journal of Haematology 2007; 139, 730–743
Once a PP is found, what further w/u should be performed?
70 y/o male with 70 y/o male with worsening tingling worsening tingling and numbness in a and numbness in a stocking distribution stocking distribution is found to have a is found to have a serum IgM lambda serum IgM lambda MM--protein of 1.1 protein of 1.1 gm/dLgm/dL..
What further tests What further tests should be done?should be done?
a.a. Skeletal surveySkeletal surveyb.b. Bone marrow Bone marrow
biopsybiopsyc.c. CT scan of C/A/PCT scan of C/A/Pd.d. All of the aboveAll of the abovee.e. b+c onlyb+c only
Once a PP is found what further w/u should be performed?
AnswerAnswerb+c onlyb+c only
Differential Dx IgMDifferential Dx IgMWMWMCLLCLLNHLNHLMGUSMGUSAmyloidosisAmyloidosis
Diagnostic testsDiagnostic testsa.a. CBC diff, platCBC diff, platb.b. Lytes, BUN, Cr, Lytes, BUN, Cr, ββ2m2mc.c. Serum viscositySerum viscosityd.d. Bone marrow biopsyBone marrow biopsye.e. CT scan of C/A/PCT scan of C/A/Pf.f. AntiAnti--MAG antibodiesMAG antibodies
(myelin(myelin--associated glycoproteins)associated glycoproteins)
a.a. Fat Pad biopsyFat Pad biopsy
Further Diagnostic Tests if IgG, IgA or IgD Paraprotein
If the finding is IgG, IgA, IgD ParaproteinIf the finding is IgG, IgA, IgD ParaproteinCBC, diff, platCBC, diff, platLytes, Bun, Cr, CaLytes, Bun, Cr, Ca2+2+, Albumin, , Albumin, ββ2 microglobulin2 microglobulinQuantitative immunoglobulins: IgG, IgM, IgAQuantitative immunoglobulins: IgG, IgM, IgASerum light chain, free assaySerum light chain, free assay24 hour urine for total protein, UPEP+IFE24 hour urine for total protein, UPEP+IFESkeletal surveySkeletal surveyBone marrow biopsyBone marrow biopsyFat Pad biopsyFat Pad biopsy
MGUS
Kyle R et al. N Engl J Med 2007;356:2582-2590
Characteristics of MGUS and Multiple Myeloma
MGUS and Outcome
Kyle and Rajkumar.Kyle and Rajkumar. Brit. J Haem 2007; 139, 730–743
MGUSUsual presentation is asymptomatic elevation of Usual presentation is asymptomatic elevation of total proteintotal proteinDiagnosis of exclusionDiagnosis of exclusion
R/O MyelomaR/O MyelomaR/O other plasma cell dyscrasiasR/O other plasma cell dyscrasias
No treatment, follow lab testsNo treatment, follow lab testsPrognosis Prognosis
Absolute protein level (higher worse)Absolute protein level (higher worse)NonNon--IgG protein (IgG better)IgG protein (IgG better)Abnormal SFLC ratioAbnormal SFLC ratio
MGUSPrognosis (Prognosis (Protein >1.5 gm/dL, non IgG, Abnl SFLCProtein >1.5 gm/dL, non IgG, Abnl SFLC))
Risk Risk RRRR Absolute risk ofAbsolute risk ofStratificationStratification Progression at 20 yrsProgression at 20 yrs
Low Risk (0 factors)Low Risk (0 factors) 11 5%5%Int Low Risk (1)Int Low Risk (1) 5.45.4 21%21%Int High Risk (2)Int High Risk (2) 10.110.1 37%37%High Risk (3)High Risk (3) 20.820.8 58%58%
Rajkumar et al.; Blood 2005. 106(3): 812Rajkumar et al.; Blood 2005. 106(3): 812--817817
MYELOMA
MyelomaMM is characterized byMM is characterized by
Increased clonal plasma cells Increased clonal plasma cells in the bone marrowin the bone marrow
Overproduction of intact Overproduction of intact monoclonal monoclonal immunoglobulins (IgG, IgA, immunoglobulins (IgG, IgA, IgD, or IgE) or BenceIgD, or IgE) or Bence--Jones Jones protein (free antibody light protein (free antibody light chains) and concomitant chains) and concomitant drop in other drop in other immunoglobulinsimmunoglobulins
Kufe. Cancer Medicine. 6th ed. 2003:2219.
Reproduced with permission from the Multiple Myeloma Research Foundation Web site. Available at: http://www.multiplemyeloma.org/about_myeloma/index.html
Multiple Myeloma : EpidemiologyApprox 19,000 new cases in US/yrApprox 19,000 new cases in US/yrPrevalence is 45Prevalence is 45--50,000 patients50,000 patients
Median Age 66 years oldMedian Age 66 years oldAge <50 years: 10%Age <40 years: 2%
Increased in African AmericansIncreased in African AmericansMales >> FemalesMales >> Females
American Cancer Society. Cancer Facts and Figures 2007. Atlanta, GA: American Cancer Society; 2007; Kufe. Cancer Medicine. 6th ed. 2003:2219; Clinical and laboratory manifestations of MM. UpToDate Web site. Available at: http://www.utdol.com/utd/content/topic.do?topicKey=plasma/2083&type=A&selectedTitle=2~80. Accessed January 2, 2007.
CRAB=symptomatic MMCRAB=symptomatic MM
Myeloma EvaluationCBC, Lytes, Cr, CaCBC, Lytes, Cr, Ca2+2+, , AlbuminAlbuminQuantitative immunoglobulins, Quantitative immunoglobulins, ββ2 microglobulin2 microglobulinSPEP, SIFE, SFLCSPEP, SIFE, SFLC24 hour urine for UPEP, UIFE24 hour urine for UPEP, UIFESkeletal survey, Skeletal survey, MRI spineMRI spineBMBx: H+E, Flow, cytogeneticsBMBx: H+E, Flow, cytogeneticsMolecular Studies: Molecular Studies: FISH, GEP, FISH, GEP, PCRPCROptional: Optional: PETPET, bone density exam, CRP, bone density exam, CRPFutureFuture: : markers for apoptosismarkers for apoptosis
Pretreatment After 4 Cycles
Plasmacytomas
Bortezomib +/- Dex:Confirmation of Remission: PET Scan
Jagannath et al. ASH 2004; Abstract 333
International Staging System (ISS)
OSOSStage I Stage I 62m62m
B2M < 3.5 mg/LB2M < 3.5 mg/LAlbumin >/= 3.5Albumin >/= 3.5
Stage II Stage II 45m45mB2M < 3.5B2M < 3.5Albumin <3.5 g/dLAlbumin <3.5 g/dL
ororB2M >/= 3.5 B2M >/= 3.5 –– 5.55.5
Stage III Stage III 29m29mB2M > 5.5B2M > 5.5
Beyond ISS: Cytogenetics and FISH
Good riskGood risknormal cytogeneticsnormal cytogeneticshyperdiploidy hyperdiploidy t(11;14)t(11;14)
Poor riskPoor riskt(4;14)t(4;14)t(14;16)t(14;16)t(14;20)t(14;20)del 17p (by FISH)del 17p (by FISH)del 13 (by metaphase del 13 (by metaphase cytogenetics)cytogenetics)hypodiploidy (by hypodiploidy (by metaphase metaphase cytogenetics)cytogenetics)LDH > 2 x ulnLDH > 2 x uln
Survival slide
U.S. Multiple Myeloma: Treatment Outline1
1. Adapted from International Myeloma Foundation; 2001. Reprinted with permission2. American Cancer Society. Cancer Facts & Figures; 2003
Asymptomatic
20
50
100
Refractory Relapse MGUS* or
SmolderingMyeloma
Active Myeloma
Plateau Remission
Symptomatic
Relapse
Therapy
~45,000~15,000New cases
in U.S.2
~11,000 deaths/yr.
in U.S.2Annual patients in the U.S.3
M P
rote
in (g
/l)
Therapy Therapy
Myeloma TreatmentAcute ManagementAcute ManagementSupportive CareSupportive CarePrimary AntiPrimary Anti--Myeloma therapyMyeloma therapy
RadiationRadiationChemotherapyChemotherapyBiologic therapyBiologic therapyAutologous TransplantationAutologous Transplantation
LongLong--Term TherapyTerm TherapyMaintenance therapyMaintenance therapy
Cure??Cure??Allogeneic TransplantationAllogeneic TransplantationCombinations of new drugs Combinations of new drugs + + autologous transplantautologous transplant
Pathophysiology
Myeloma Treatment
Acute ManagementAcute ManagementInfections: humoral and cellInfections: humoral and cell--mediated deficitsmediated deficits
Antibiotics/AntiviralsAntibiotics/Antivirals•• Encapsulated organisms (pneumococcus)Encapsulated organisms (pneumococcus)•• Viral infections (zoster)Viral infections (zoster)•• Pneumocystis CariniPneumocystis Carini
Vaccines (esp. pneumococcal, varicella)Vaccines (esp. pneumococcal, varicella)
Pain MedicationsPain MedicationsHypercalcemia (bisphosphonates)Hypercalcemia (bisphosphonates)Renal Insufficiency ( HD, plasma exchange (?))Renal Insufficiency ( HD, plasma exchange (?))Cord compression (Surgery, XRT, steroids)Cord compression (Surgery, XRT, steroids)
Multiple Myeloma – Supportive Care
NeuropathyNeuropathy30% have PN at diagnosis30% have PN at diagnosisSensory>motorSensory>motorMany MM drugs cause PNMany MM drugs cause PNPreventativesPreventatives
AlphaAlpha--lipoic acidlipoic acidLL--carnitinecarnitineVit B6Vit B6
Treat PainTreat PainGabapentinGabapentinDuloxetine (Cymbalta)Duloxetine (Cymbalta)Amitriptyline (Elavil)Amitriptyline (Elavil)Pregabalin (Lyrica)Pregabalin (Lyrica)NarcoticsNarcotics
Bone Directed TherapyBone Directed TherapyVit D/ Ca2+Vit D/ Ca2+Avoid Steroids (?)Avoid Steroids (?)BisphosphonatesBisphosphonates
Zoledronic acidZoledronic acidPamidronatePamidronateUniversally givenUniversally givenBest for those with BDBest for those with BD? some anti? some anti--MM effectsMM effects
Side EffectsSide EffectsRenal insufficiencyRenal insufficiencyOsteonecrosis of JawOsteonecrosis of Jaw
•• Avoid surgeryAvoid surgery•• AntibioticsAntibiotics•• Limit duration ofLimit duration of BPBP
Multiple Myeloma Treatment 1990’s Response Rate and Median Survival
MPMP 4040 3030VADVAD 5555 3030DexamethasoneDexamethasone 4040 3030M2 ProtocolM2 Protocol 7070 3030InterferonInterferon 2020
NO CRNO CR’’ss
Initial Treatment % Response Median Survival (Months)
Initial Therapy for Myeloma: 2000’s +Rapidly EvolvingRapidly Evolving
5 Active treatments5 Active treatmentsThalidomideThalidomideLenalidomideLenalidomideBortezomibBortezomibPegylated Liposomal Doxorubicin (PLD)Pegylated Liposomal Doxorubicin (PLD)Autologous Stem Cell TransplantAutologous Stem Cell Transplant
Many New AgentsMany New AgentsCarfilzomibCarfilzomibPomalidomidePomalidomide
CombinationsCombinations
Two Important Classes of Drugs for MMIMID: Immune modulatory drugsIMID: Immune modulatory drugs
MOA remains to be fully characterizedMOA remains to be fully characterizedProPro--apoptotic propertiesapoptotic propertiesAntiAnti--angiogenic propertiesangiogenic propertiesInhibits the secretion of proInhibits the secretion of pro--inflammatory cytokinesinflammatory cytokines
Thalidomide, Lenalidomide, PomalidomideThalidomide, Lenalidomide, Pomalidomide
Proteasome InhibitorsProteasome InhibitorsMOA remains to be fully elucidatedMOA remains to be fully elucidated
Reversible inhibitor of the proteasomeReversible inhibitor of the proteasomeInhibits NFInhibits NFκκ--BBProPro--ApoptoticApoptoticAffects unfolded protein responseAffects unfolded protein response
Bortezomib, CarfilzomibBortezomib, Carfilzomib
Lenalidomide: Treatment ResponsesRelapse and RefractoryRelapse and Refractory
CR ~5%CR ~5%PR ~30PR ~30--40%40%
Upfront/FirstUpfront/First--line therapyline therapyBest when combined with steroids (Dexamethasone)Best when combined with steroids (Dexamethasone)
CR 20CR 20--30%30%PR ~90% PR ~90%
In combination with Biaxin + DexamethasoneIn combination with Biaxin + DexamethasoneCR 40%CR 40%PR 95%PR 95%
Dexamethasone 40 mg given once weekly (pulse Dexamethasone 40 mg given once weekly (pulse dexamethasone (4 days in a row) increases toxicity)dexamethasone (4 days in a row) increases toxicity)Must anticoagulateMust anticoagulate
Bortezomib and Proteasome Inhibition1-3
α β
19SCap
20SSubunit
Chymo-tryptic
Site
Post-glutamyl
Site
TrypticSite
β1 β2
β3
β4
β5
β6
β7
26S Proteasome
• Degrades ubiquitinated proteins• Proteolysis is adenosine triphosphate
(ATP) dependent
Bortezomib
19SCap
• Chymotryptic site is rate limiting in protein degradation
1. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338.2. DeMartino GN, Slaughter CA. J Biol Chem. 1999;274:22123-22126.3. Seemuller E, et al. Science. 1995;268:579-582.
Bortezomib: Treatment ResponsesRelapse and RefractoryRelapse and Refractory
CR ~9%CR ~9%PR ~30PR ~30--40%40%
Upfront/FirstUpfront/First--line therapyline therapyBest when combined with steroids Best when combined with steroids (Dexamethasone)(Dexamethasone)
CR 10CR 10--20%20%PR ~90% PR ~90%
In combination with Doxil +/In combination with Doxil +/-- DexamethasoneDexamethasoneCR 35CR 35--40%40%PR >90%PR >90%
In combination with Thalidomide/Revlimid +/In combination with Thalidomide/Revlimid +/-- DexDexCR 30CR 30--40%40%PR 100%PR 100%
Multiple Myeloma Treatment 2000’sResponse Rate and Median Survival
MPTMPT >90%>90% ~7~7--20%20% 45m45mBort/DexBort/Dex 8585--9090 ~10%~10% ??Len/DexLen/Dex >90%>90% ~20%~20% ??Thal/Bort/DexThal/Bort/Dex >90%>90% ~30%~30% ??PADPAD >90% ~25% >90% ~25% ??VDDVDD >90% ~25%>90% ~25% ??RVDRVD >95%>95% ~20~20--25%25% ??
Initial Treatment % Response %CR Median Survival (Months)
Myeloma Survival by Decade
ImprovedImproveddue to newdue to newdrugs: drugs:
ThalidomideThalidomideLenalidomideLenalidomideBortezomibBortezomib
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