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Multiple Myeloma 2010Multiple Myeloma 2010

Wael Harb MDWael Harb MDHorizon Oncology CenterHorizon Oncology Center

Overview Overview

Introduction: epidemiology, clinical Introduction: epidemiology, clinical presentation, diagnosis, stagingpresentation, diagnosis, staging

Autologous stem cell transplantationAutologous stem cell transplantation Initial approaches to treatmentInitial approaches to treatment

• Current optionsCurrent options• Novel agents and combinationsNovel agents and combinations

Considerations in non-transplantation-Considerations in non-transplantation-eligible patientseligible patients

Prevention of skeletal complicationsPrevention of skeletal complications

What is MM?What is MM?

Multiple myeloma (MM) is Multiple myeloma (MM) is characterized by the neoplastic characterized by the neoplastic proliferation of a single clone of proliferation of a single clone of plasma cells producing a monoclonal plasma cells producing a monoclonal immunoglobulin.immunoglobulin.

Plasma CellPlasma Cell

Multiple Myeloma: IncidenceMultiple Myeloma: Incidence

The lifetime risk of getting MM is 1 in 159 The lifetime risk of getting MM is 1 in 159 (0.63%).(0.63%).

20,180 new cases will be diagnosed in 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in 2010 (11,170 in men and 9,010 in women)women)

10,650 deaths are expected to occur in 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women)2010 (5,760 in men and 4,890 in women)

The 5-year relative survival rate for MM The 5-year relative survival rate for MM is around 35%is around 35%

IncidenceIncidence

MM occurs in all races and all MM occurs in all races and all geographic locationsgeographic locations

African Americans and blacks from African Americans and blacks from Africa is two to three times the risk in Africa is two to three times the risk in whiteswhites

Risk is lower in Asians from Japan and Risk is lower in Asians from Japan and in Mexicansin Mexicans

Slightly more frequent in men than in Slightly more frequent in men than in women (1.4:1)women (1.4:1)

AgeAge

MM is a disease of older adultsMM is a disease of older adults The median age at diagnosis is 66 The median age at diagnosis is 66

yearsyears Only 10 percent of patients are Only 10 percent of patients are

younger than 50 yearsyounger than 50 years Only 2 percent of patients are Only 2 percent of patients are

younger than 40 yearsyounger than 40 years

MM: Clinical PresentationsMM: Clinical Presentations

Anemia - 73 percentAnemia - 73 percent Bone pain - 58 percentBone pain - 58 percent Elevated creatinine - 48 percentElevated creatinine - 48 percent Fatigue/generalized weakness - 32 Fatigue/generalized weakness - 32

percentpercent Hypercalcemia- 28 percentHypercalcemia- 28 percent Weight loss - 24 percent, one-half of Weight loss - 24 percent, one-half of

whom had lost ≥ 9 kgwhom had lost ≥ 9 kg

Multiple Myeloma = M-CRABMultiple Myeloma = M-CRAB

Monoclonal proteinMonoclonal protein CalciumCalcium Renal failureRenal failure AnemiaAnemia Bone pain with lytic lesionsBone pain with lytic lesions

ImmunoglobulinImmunoglobulin

ImmunoglobulinsImmunoglobulins

SPEP: NormalSPEP: Normal

SPEP: M-protein, M-spikeSPEP: M-protein, M-spike

Renal FailureRenal Failure

Cast nephropathy (also called Cast nephropathy (also called myeloma kidney) from light chainsmyeloma kidney) from light chains

HypercalcemiaHypercalcemia Light chain amyloidosisLight chain amyloidosis Drug-induced renal damageDrug-induced renal damage

AnemiaAnemia

Normocytic, normochromic anemiais Normocytic, normochromic anemiais present in 73% at diagnosis and in present in 73% at diagnosis and in 97%at some time during the course 97%at some time during the course of the diseaseof the disease

This anemia can be related to:This anemia can be related to:• Bone marrow replacementBone marrow replacement• Kidney damageKidney damage• Dilution in the case of a large M-proteinDilution in the case of a large M-protein• B12 deficiency in 14%B12 deficiency in 14%

Rouleaux Formation Rouleaux Formation

Lytic Bone LesionLytic Bone Lesion

MM: PET ScanMM: PET Scan

Extramedullary PlasmacytomaExtramedullary Plasmacytoma

Differential Diagnosis of MM Differential Diagnosis of MM

Monoclonal gammopathy of Monoclonal gammopathy of undetermined significance (MGUS)undetermined significance (MGUS)

Smoldering multiple myeloma (SMM)Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemiaWaldenstrom macroglobulinemia Solitary plasmacytomaSolitary plasmacytoma Primary amyloidosis (AL)Primary amyloidosis (AL) POEMS syndromePOEMS syndrome Metastatic carcinomaMetastatic carcinoma

Multiple Myeloma Multiple Myeloma

All 3 criteria must be met:All 3 criteria must be met:1.1. Presence of a serum or urinary Presence of a serum or urinary

monoclonal proteinmonoclonal protein2.2. Presence of clonal plasma cells in the Presence of clonal plasma cells in the

bone marrow or a plasmacytomabone marrow or a plasmacytoma3.3. Presence of end organ damage felt Presence of end organ damage felt

related to the plasma cell dyscrasia, such related to the plasma cell dyscrasia, such as:as:• Increased calcium concentrationIncreased calcium concentration• Lytic bone lesionsLytic bone lesions• AnemiaAnemia• Renal failureRenal failure

Smoldering Multiple Myeloma Smoldering Multiple Myeloma SMM, AsymptomaticSMM, Asymptomatic

Both criteria must be met:Both criteria must be met: Serum monoclonal protein ≥3 g/dL Serum monoclonal protein ≥3 g/dL

and/or bone marrow plasma cells and/or bone marrow plasma cells ≥10 percent≥10 percent

No end organ damage related to No end organ damage related to plasma cell dyscrasiaplasma cell dyscrasia

Monoclonal Gammopathy of Monoclonal Gammopathy of Undetermined Significance Undetermined Significance

(MGUS)(MGUS)

All 3 criteria must be met:All 3 criteria must be met: Serum monoclonal protein <3 g/dLSerum monoclonal protein <3 g/dL Bone marrow plasma cells <10 Bone marrow plasma cells <10

percentpercent No end organ damage related to No end organ damage related to

plasma cell dyscrasia or a related B plasma cell dyscrasia or a related B cell lymphoproliferative disordercell lymphoproliferative disorder

POEMS SyndromePOEMS Syndrome

Osteosclerotic myelomaOsteosclerotic myeloma• PolyneuropathyPolyneuropathy• OrganomegalyOrganomegaly• EndocrinopathyEndocrinopathy• Monoclonal proteinMonoclonal protein• Skin changesSkin changes

MM: EvaluationMM: Evaluation

CBC and differential,peripheral blood smearCBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, Chemistry:serum calcium, creatinine,

albumin, LDH , beta-2 microglobulin, and C-albumin, LDH , beta-2 microglobulin, and C-reactive proteinreactive protein

Serum protein electrophoresis (SPEP) + IFSerum protein electrophoresis (SPEP) + IF Quantification of immunoglobulinsQuantification of immunoglobulins Urinalysis and a 24-hour urine collection for Urinalysis and a 24-hour urine collection for

electrophoresis (UPEP) + IFelectrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC)Serum free monoclonal light chain (FLC)

MM EvaluationMM Evaluation

Serum viscosity should be measured if the M-Serum viscosity should be measured if the M-protein concentration is high protein concentration is high

Bone marrow aspiration and biopsy with Bone marrow aspiration and biopsy with immunophenotyping, conventional immunophenotyping, conventional cytogenetics, and fluorescence in situ cytogenetics, and fluorescence in situ hybridization (FISH)hybridization (FISH)

Metastatic bone survey with plain Metastatic bone survey with plain radiographs including the humeri and femoral radiographs including the humeri and femoral bones should be performed in all patients. bones should be performed in all patients.

MRI, CT, or PET/CTMRI, CT, or PET/CT

Bone MarrowBone Marrow

Cytogenenetics, Interphase Cytogenenetics, Interphase FISHFISH

Poor prognosis (median survival 25 Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)months): t(4;14)(p16;q32), t(14;16)(q32;q23), and (q32;q23), and

-17p13-17p13 Intermediate prognosis (median Intermediate prognosis (median

survival 42 months): -13q14survival 42 months): -13q14 Good prognosis (median survival 50 Good prognosis (median survival 50

months): all othersmonths): all others

Staging for MMStaging for MM

International staging system (ISS) International staging system (ISS) 

Stage I — B2M <3.5 mg/L and serum Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dLalbumin ≥3.5 g/dL

Stage II — neither stage I nor stage IIIStage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/LStage III — B2M ≥5.5 mg/L

Median overall survival for patients Median overall survival for patients with ISS stages I, II, and III are 62, with ISS stages I, II, and III are 62, 44, and 29 months44, and 29 months

MM: Treatment DecisionsMM: Treatment Decisions

Indications for treatmentIndications for treatment Risk stratificationRisk stratification Eligibility for stem cell Eligibility for stem cell

transplantationtransplantation

Smoldering (asymptomatic) Smoldering (asymptomatic) myelomamyeloma

Deferral of chemotherapy until Deferral of chemotherapy until progression to symptomatic diseaseprogression to symptomatic disease

Follow these patients closely, every 3 Follow these patients closely, every 3 to 4 months, with serum protein to 4 months, with serum protein electrophoresis, complete blood count, electrophoresis, complete blood count, serum creatinine, and serum calciumserum creatinine, and serum calcium

Metastatic bone survey should be Metastatic bone survey should be considered annually because considered annually because asymptomatic bone lesions may asymptomatic bone lesions may developdevelop

MM: Indications for TreatmentMM: Indications for Treatment

Anemia (hemoglobin <10 g/dL or 2 Anemia (hemoglobin <10 g/dL or 2 g/dL below normal)g/dL below normal)

Hypercalcemia (serum calcium >11.5 Hypercalcemia (serum calcium >11.5 mg/dL)mg/dL)

Renal insufficiency (serum Renal insufficiency (serum creatinine>2 mg/dL)creatinine>2 mg/dL)

Lytic bone lesions or severe Lytic bone lesions or severe osteopeniaosteopenia

Extramedullary plasmacytomaExtramedullary plasmacytoma

MM: RISK STRATIFICATIONMM: RISK STRATIFICATION

FISH for detection of t(4;14), t(14;16), and FISH for detection of t(4;14), t(14;16), and del17p13del17p13

Conventional cytogenetics (karyotyping) Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidyfor detection of del 13 or hypodiploidy

The presence of any of the above markers The presence of any of the above markers defines high risk myeloma, which defines high risk myeloma, which encompasses the 25 percent of MM encompasses the 25 percent of MM patients who have a median survival of patients who have a median survival of approximately two years or less despite approximately two years or less despite standard treatmentstandard treatment

Current Frontline OptionsCurrent Frontline Options

Conventional chemotherapyConventional chemotherapy• Survival Survival ≤ 3 yrs≤ 3 yrs

TransplantationTransplantation• Prolongs survival 4-5 yrsProlongs survival 4-5 yrs

Novel agents targeting stromal Novel agents targeting stromal interactions and associated signaling interactions and associated signaling pathways have shown promisepathways have shown promise

Chng WJ, et al. Cancer Control. 2005;12:91-104.

MM: INITIAL THERAPYMM: INITIAL THERAPY

The initial therapy of patients with The initial therapy of patients with symptomatic myeloma varies symptomatic myeloma varies depending on whether patients are depending on whether patients are eligible or not to pursue autologous eligible or not to pursue autologous hematopoietic cell transplantation hematopoietic cell transplantation

*Thal/dex or dex are additional options especially if immediate response is needed.

Clearly not transplantation candidate based on age, performance

score, and comorbidity

MPT, MPV, Len/dexor clinical trial*

Potential transplantation candidate

Nonalkylator-based induction x 4 cycles

Stem cell harvest

Initial Approach to Treatment of Initial Approach to Treatment of MMMM

DETERMINING TRANSPLANT DETERMINING TRANSPLANT ELIGIBILITYELIGIBILITY

Autologous hematopoietic cell transplantation Autologous hematopoietic cell transplantation (HCT) results in superior event-free and (HCT) results in superior event-free and overall survival rates when compared with overall survival rates when compared with combination chemotherapycombination chemotherapy

All patients should be evaluated at diagnosis All patients should be evaluated at diagnosis for transplant eligibility so that the risks and for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed benefits of autologous HCT can be reviewed with those eligiblewith those eligible

A minority of patients will be eligible for A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigationalapproaches in myeloma remain investigational

NOT Eligible for Autologous NOT Eligible for Autologous HCT HCT

Age >77 yearsAge >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter)Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 Serum creatinine>2.5 mg/dL (221

µmol/liter) unless on chronic stable dialysisµmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group Eastern Cooperative Oncology Group

(ECOG) performance status 3 or 4 unless (ECOG) performance status 3 or 4 unless due to bone paindue to bone pain

New York Heart Association functional New York Heart Association functional status Class III or IVstatus Class III or IV

54

42

Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883.

15 30 45 60

25

50

75

100

OS

(%)

00

High dose

Conventional dose

Mos20 40 60 80

25

50

75

100

Surv

ival

(%)

00

Intensive therapy

Standard therapy

Mos

P = .03 by Wilcoxon testP = .04 by log-rank test

Transplantation vs Conventional Transplantation vs Conventional ChemotherapyChemotherapy

Autologous Stem Cell Autologous Stem Cell TransplantationTransplantation

Mel 200 mg/mMel 200 mg/m22 standard conditioning regimen standard conditioning regimen Sufficient performance score, and adequate liver, Sufficient performance score, and adequate liver,

pulmonary, cardiac function neededpulmonary, cardiac function needed Higher PR and CR rates than conventional Higher PR and CR rates than conventional

chemotherapychemotherapy Higher OS and EFS than conventional RxHigher OS and EFS than conventional Rx Advanced age and impaired renal function are, by Advanced age and impaired renal function are, by

themselves, not contraindicationsthemselves, not contraindications

Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010.

Stem Cell TransplantationStem Cell Transplantation

Key issuesKey issues Efficacy compared with conventional chemotherapyEfficacy compared with conventional chemotherapy Timing: early vs delayedTiming: early vs delayed Single vs tandemSingle vs tandem Role of allogeneic and miniallogeneic transplantationsRole of allogeneic and miniallogeneic transplantations Maintenance post-SCTMaintenance post-SCT

Novel Frontline OptionsNovel Frontline Options

Immunomodulatory drugs (IMiDs)Immunomodulatory drugs (IMiDs)• ThalidomideThalidomide• LenalidomideLenalidomide

Proteasome inhibitorsProteasome inhibitors• BortezomibBortezomib• CarfilzomibCarfilzomib

Kyle RA, et al. N Engl J Med. 2004;351:1860-1873.Copyright ©2004. Massachusetts Medical Society. All rights reserved.

Proposed Mechanism of Action for Proposed Mechanism of Action for Multiple Myeloma TherapiesMultiple Myeloma Therapies

Thalidomide: Thalidomide: Proposed Mechanism of ActionProposed Mechanism of Action

Proposed mechanismsProposed mechanisms• Inhibition of TNF-Inhibition of TNF-• Suppression of angiogenesisSuppression of angiogenesis• Increase in cell-mediated cytotoxic Increase in cell-mediated cytotoxic

effectseffects• Modulation of adhesion molecule Modulation of adhesion molecule

expressionexpression

Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085.

LenalidomideLenalidomide

Immunomodulatory derivative of Immunomodulatory derivative of thalidomide thalidomide

More potent than thalidomide in preclinical More potent than thalidomide in preclinical modelsmodels• Dose-dependent decrease in TNF-Dose-dependent decrease in TNF-αα and and

interleukin-6 interleukin-6 • Directly induces apoptosis, G1 growth arrestDirectly induces apoptosis, G1 growth arrest• Enhances activity of dexamethasoneEnhances activity of dexamethasone

More favorable toxicity profile than More favorable toxicity profile than thalidomidethalidomide

Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950.

Bortezomib:Bortezomib:A Reversible Proteasome InhibitorA Reversible Proteasome Inhibitor

Chymo-tryptic

Site

Post-Glutamyl

Site

TrypticSite

b1 b2

3

4

b5

6

7

Cross section of ring

Bortezomib

Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338.

H N B

N H

O

O

OHN

N

OH

Initial Approach to Treatment of MMInitial Approach to Treatment of MM

Clearly not a transplantation candidate

MPT, MPV, Len/dexor clinical trial*

Potential transplantation candidate

Nonalkylator-based induction

Stem cell harvest

Melphalan/Prednisone/ThalidomideMelphalan/Prednisone/Thalidomide

Palumbo A, et al. Blood. 2008;112:3107-3114.

OutcomeOutcome

Melphalan/Melphalan/PrednisonePrednisone

(n = 164)(n = 164)

Melphalan/Melphalan/Prednisone/Prednisone/ThalidomideThalidomide

(n = 167)(n = 167)

HR (95% CI)HR (95% CI) PP Value Value

Median PFS, mosMedian PFS, mos 14.514.5 21.821.8 0.63 (0.48-0.81)0.63 (0.48-0.81) .0004.0004No. of eventsNo. of events 125125 111111 ---- ----

Median OS, mosMedian OS, mos 47.647.6 45.045.0 1.04 (0.76-1.44)1.04 (0.76-1.44) .79.79No. of eventsNo. of events 7070 7777 ---- ----

Lenalidomide 25 mg/day PO on Days 1-21 +

High-dose Dex 40 mg/day PO on Days 1-4, 9-12, 17-20

(n = 223)

Lenalidomide 25 mg/day PO on Days 1-21 +

Low-dose Dex 40 mg/day PO on Days 1, 8, 15, 22

(n = 222)

Len + High or Low-Dose Dex in Len + High or Low-Dose Dex in Newly Diagnosed Myeloma (E4A03)Newly Diagnosed Myeloma (E4A03)

Courses repeat every 28 days ≤ 1 yr in absence of PD or unacceptable toxicity

Total Dex dose per cycle:480 mg

Untreated, symptomatic

myeloma, no age cutoff

Total Dex dose per cycle:160 mg

Rajkumar SV, et al. ASCO 2008. Abstract 8504. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37

Len + High or Low-Dose Dex Len + High or Low-Dose Dex (E4A03): Response(E4A03): Response

3-yr OS rates converged (3-yr OS rates converged (PP = .467) with all pts crossed over to low dose = .467) with all pts crossed over to low dose Successful stem cell harvesting in 97.6% (n = 167)Successful stem cell harvesting in 97.6% (n = 167) 3-yr OS for 3-yr OS for high dosehigh dose or or low doselow dose followed by SCT: 92% followed by SCT: 92%

High DoseHigh Dose Low DoseLow Dose PP Value Value

Overall response at 4 cycles, %Overall response at 4 cycles, % 7979 6868 .008.008

≥ ≥ VGPR within 4 cycles, %VGPR within 4 cycles, % 4242 2424 < .0001< .0001

Best overall response, %Best overall response, % 8181 7070 .009.009

≥ ≥ VGPR, %VGPR, % 5050 4040 .040.040

CR (IF-), %CR (IF-), % 1313 1010 ----

OS, %OS, %

1-yr OS1-yr OS 8787 9696 .0002.0002

2-yr OS2-yr OS 7575 8787 ----

Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.

Len + High or Low-Dose Dex Len + High or Low-Dose Dex (E4A03): Adverse Events(E4A03): Adverse Events

Toxicity Grade Toxicity Grade ≥ 3, %≥ 3, % High DoseHigh Dose Low DoseLow Dose PP Value Value

Toxicity (any)Toxicity (any) during first 4 during first 4 mosmos, grade , grade ≥ 3≥ 3 5252 3535 .0001.0001

Nonhematologic (any), Nonhematologic (any), grade grade ≥ 3≥ 3 6565 4848 .0002.0002

Death (early < 4 mos)Death (early < 4 mos) 55 0.500.50 .003.003

DVT/PEDVT/PE 2626 1212 .0003.0003

Infection/pneumoniaInfection/pneumonia 1616 99 .04.04

NeutropeniaNeutropenia 1212 2020 .02.02

Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.

Lenalidomide Dosing for MM and Lenalidomide Dosing for MM and Impaired Renal FunctionImpaired Renal Function

Renal Impairment (CrCl)Renal Impairment (CrCl) Lenalidomide DosageLenalidomide Dosage

Moderate (30 to < 60 mL/min)Moderate (30 to < 60 mL/min) 10 mg QD10 mg QD

Severe (< 30 mL/min, not requiring Severe (< 30 mL/min, not requiring dialysis)dialysis) 15 mg Q 48 hrs15 mg Q 48 hrs

ESRD (< 30 mL/min, requiring dialysis)ESRD (< 30 mL/min, requiring dialysis) 5 mg QD5 mg QDOn dialysis days, On dialysis days,

administer following administer following dialysisdialysis

Lenalidomide [package insert].

Peripheral Neuropathy Following Peripheral Neuropathy Following Bortezomib Therapy in Advanced Bortezomib Therapy in Advanced

MMMMPeripheral neuropathy was reported in Peripheral neuropathy was reported in 90/256 (35%) patients with MM treated 90/256 (35%) patients with MM treated with bortezomib in phase II trialswith bortezomib in phase II trials80% of patients entered these trials with preexisting 80% of patients entered these trials with preexisting peripheral neuropathyperipheral neuropathy3% patients without vs 16% with baseline peripheral 3% patients without vs 16% with baseline peripheral neuropathy developed grade 3 peripheral neuropathyneuropathy developed grade 3 peripheral neuropathy

Richardson PG, et al. ASH 2003. Abstract 512.

Frontline Therapy in Elderly MM Frontline Therapy in Elderly MM PatientsPatients

For elderly patients or those who are not suitable For elderly patients or those who are not suitable candidates for transplantation, MP has been a candidates for transplantation, MP has been a standard treatmentstandard treatment• ORR: 60%ORR: 60%• Long-term CR: < 5%Long-term CR: < 5%

Trials with MP-based combinations reported Trials with MP-based combinations reported improved response rates and time to progressionimproved response rates and time to progression• MPTMPT• VMPVMP

NCCN Practice Guidelines. Myeloma. V.3.2010.

ConclusionsConclusions In elderly patients, the addition of novel In elderly patients, the addition of novel

agents to standard MP has provided improved agents to standard MP has provided improved response ratesresponse rates• MP alone (ORR: 50%; CR: 5%)MP alone (ORR: 50%; CR: 5%)• MPR (50% to 95% reduction in myeloma protein in MPR (50% to 95% reduction in myeloma protein in

55.6%)55.6%)• VMP (ORR: 86%)VMP (ORR: 86%)

Care should be taken with IMiD-based therapy Care should be taken with IMiD-based therapy to include aspirin prophylaxis for DVT/PEto include aspirin prophylaxis for DVT/PE

Care should be taken with bortezomib-based Care should be taken with bortezomib-based regimens to include herpes zoster prophylaxisregimens to include herpes zoster prophylaxis

MM & Skeletal ComplicationsMM & Skeletal Complications

~ 80% of patients with ~ 80% of patients with multiple myeloma will multiple myeloma will have evidence of have evidence of skeletal involvement skeletal involvement on skeletal surveyon skeletal survey• Vertebrae: 65%Vertebrae: 65%• Ribs: 45%Ribs: 45%• Skull: 40%Skull: 40%• Shoulders: 40%Shoulders: 40%• Pelvis: 30%Pelvis: 30%• Long bones: 25% Long bones: 25%

Dimopoulos M, et al. Leukemia. 2009:1-12.

The Central Role of the The Central Role of the Osteoclast in Osteoclast in Osteolytic Bone Osteolytic Bone

Destruction Destruction

Growthfactors

Osteoclast differentiation

Osteolysis

Direct effects on osteoclast differentiation

Tumor cells

Bone loss

Activeosteoclast

Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664.

Mechanism of Bisphosphonate Mechanism of Bisphosphonate Inhibition of Osteoclast ActivityInhibition of Osteoclast Activity

Bisphosphonates inhibit osteoclast activity, and promote osteoclast apoptosis[1]

Bisphosphonates are released locally during bone resorption[1]

Bisphosphonates are

concentrated under osteoclasts[1]

Bisphosphonates may modulate signaling from osteoblasts to osteoclasts

New bone

X

Bone

Increased OPG production[2]

Decreased RANKL expression[3]

1. Reszka AA, et al. Curr Rheumatol Rep. 2003;5:65-74. 2. Viereck V, et al. Biochem Biophys Res Commun. 2002;291:680-686. 3. Pan B, et al. J Bone Miner Res. 2004;19:147-154.

Recommended Doses and Recommended Doses and Infusion TimesInfusion Times

DrugDrug Dose/Infusion Dose/Infusion TimeTime

IntervalInterval

Estimated CrCl > 60 mL/minEstimated CrCl > 60 mL/min

PamidronatePamidronateZoledronic acidZoledronic acid

90 mg over 2-3 hrs90 mg over 2-3 hrs4 mg over 15 mins4 mg over 15 mins

3-4 wks3-4 wks3-4 wks3-4 wks

Estimated CrCl 30 to < 60 mL/minEstimated CrCl 30 to < 60 mL/min

PamidronatePamidronateZoledronic acidZoledronic acid

90 mg over 2-3 90 mg over 2-3 hrs*hrs*

Reduced dosageReduced dosage††

3-4 wks3-4 wks3-4 wks3-4 wks

Estimated CrCl < 30 mL/minEstimated CrCl < 30 mL/min

PamidronatePamidronateZoledronic acidZoledronic acid

90 mg over 4-6 90 mg over 4-6 hrs*hrs*

Not recommendedNot recommended

3-4 wks3-4 wks*Consider dose reduction .†3.5mg (CrCl 50-60 mL/min); 3.3 mg (CrCl 40-49 mL/min); 3.0 mg (CrCl 30-39 mL/min).

Kyle R, et al. J Clin Oncol. 2007;25:2464-2472.

Bisphosphonates and Bisphosphonates and OsteonecrosisOsteonecrosis

Uncommon complication Uncommon complication causing avascular causing avascular necrosis of maxilla necrosis of maxilla or mandible or mandible

Suspect with tooth or jaw Suspect with tooth or jaw pain or exposed bone pain or exposed bone

May be related to May be related to duration of therapyduration of therapy

True incidence unknownTrue incidence unknown

Papapetrou PD. Hormones (Athens). 2009;8:96-110.

Normal RANKL/OPG Normal RANKL/OPG

Prevents Promotes

Osteoclastic Activity

RANKLOPG

Hofbauer LC, et al. JAMA. 2004;292:490-495.

The RANK/RANKL/OPG The RANK/RANKL/OPG Pathway in Osteolytic Bone Pathway in Osteolytic Bone

Disease Disease

Prevents Promotes

Increased osteoclastic activity and

decreased OPG

OPG RANKL

Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664.

Denosumab: Inhibiting RANK in Denosumab: Inhibiting RANK in Bone DiseaseBone Disease

High affinity human monoclonal High affinity human monoclonal antibody that binds RANKLantibody that binds RANKL

Administered via SC injectionAdministered via SC injection Specific: does not bind to TNF-Specific: does not bind to TNF-αα, TNF-, TNF-

ββ, TRAIL, or CD40L, TRAIL, or CD40L Inhibits formation and activation of Inhibits formation and activation of

osteoclastsosteoclasts

Multiple Myeloma = M-CRABMultiple Myeloma = M-CRAB

Monoclonal proteinMonoclonal protein CalciumCalcium Renal failureRenal failure AnemiaAnemia Bone pain with lytic lesionsBone pain with lytic lesions

Thank youThank you