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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