Esperienza clinica con le Esperienza clinica con le antracicline liposomiali nel MMantracicline liposomiali nel MM

Massimo OffidaniMassimo Offidani

Clinica di EmatologiaClinica di EmatologiaAzienda Ospedaliero-UniversitariaAzienda Ospedaliero-Universitaria

Ospedali Riuniti di AnconaOspedali Riuniti di Ancona

Effect of single drug doxorubicin in MMEffect of single drug doxorubicin in MM

9 rel/ref MM pts: 1 PR and 1 MR9 rel/ref MM pts: 1 PR and 1 MR(Alberts DS et al: (Alberts DS et al: Cancer Chem Rep, 1975Cancer Chem Rep, 1975))

Review of literature rel/ref MM: 5% PRReview of literature rel/ref MM: 5% PR(Rodjer S et al: (Rodjer S et al: Haemat J, 2000Haemat J, 2000))

Effect of doxorubicin combinations in MMEffect of doxorubicin combinations in MM

VAD: PR=50-65%, VGPR=15%, CR/nCR=4-8% VAD: PR=50-65%, VGPR=15%, CR/nCR=4-8%

Anthracyclines in Multiple MyelomaAnthracyclines in Multiple Myeloma

• Doxorubicin is one of the most potent antibiotics used in tumor Doxorubicin is one of the most potent antibiotics used in tumor

chemotherapychemotherapy

• Longer exposure to higher concentrations results in higher Longer exposure to higher concentrations results in higher

plasma cell killplasma cell kill

• Short half life have negative impact on the administration Short half life have negative impact on the administration

modalitymodality

• Total cumulative effect limits its use in chronic disease processesTotal cumulative effect limits its use in chronic disease processes

Rationale for Pegylated Rationale for Pegylated Liposomal Doxorubicin in MMLiposomal Doxorubicin in MM

•Increased angiogenesis in BM of MM patientsIncreased angiogenesis in BM of MM patients

•Longer plasma half lifeLonger plasma half life

•Possible more effective against MDR positive cellsPossible more effective against MDR positive cells

•Improved safety profile compared to free doxorubicinImproved safety profile compared to free doxorubicin

•Outpatient regimenOutpatient regimen

• CAELYX has a favorable safety profileCAELYX has a favorable safety profile

• Phase III DVd Phase III DVd vsvs VAd VAd

– RR, PFS, OS similarRR, PFS, OS similar• Significantly less neutropenia (10 Significantly less neutropenia (10 vsvs 24%) 24%)• Alopecia (20 Alopecia (20 vsvs 44%) 44%)• Less supportive care (CVA, GFs)Less supportive care (CVA, GFs)

– DVd regimen decreased angiogenic activity in BMDVd regimen decreased angiogenic activity in BM

• Need for modifying anthracycline-based regimens with the Need for modifying anthracycline-based regimens with the addition of new-drugsaddition of new-drugs– Thalidomide, LenalidomideThalidomide, Lenalidomide– BortezomibBortezomib

Rifkin et al. Rifkin et al. CancerCancer. 2006;106:848-858 . 2006;106:848-858 Hussein et al. Hussein et al. Clin Lymphoma MyelomaClin Lymphoma Myeloma. 2007;7(suppl 4):S145-S149. 2007;7(suppl 4):S145-S149

Why CAELYX in Multiple Myeloma?

Preclinical rationale for Pegylated Liposomal Preclinical rationale for Pegylated Liposomal Doxorubicin + IMiDs in MMDoxorubicin + IMiDs in MM

Different but complementary mechanism of actionDifferent but complementary mechanism of action

• Both antiangiogenicBoth antiangiogenic

• Both cytotoxic effect with different mechanismBoth cytotoxic effect with different mechanism

• IMiDs target microenvironmentIMiDs target microenvironment

• IMiDs exert immune activation effectIMiDs exert immune activation effect

• Nonoverlapping toxicitiesNonoverlapping toxicities

Preclinical Rationale for Combining Preclinical Rationale for Combining CAELYX + BortezomibCAELYX + Bortezomib

• Additive or synergistic effects are seen in both Additive or synergistic effects are seen in both in in vitrovitro1,2,31,2,3 and and in vivoin vivo44 model systems model systems

• Interactions occur through multiple pathways to Interactions occur through multiple pathways to enhance anti-tumor efficacyenhance anti-tumor efficacy

– Bortezomib abrogates anthracycline resistanceBortezomib abrogates anthracycline resistance

• NF-kBNF-kB1,21,2, Bcl-2, P-glycoprotein, DNA damage , Bcl-2, P-glycoprotein, DNA damage repairrepair33

– Anthracyclines abrogate bortezomib resistanceAnthracyclines abrogate bortezomib resistance

• Suppression of stress response protein MKP-1Suppression of stress response protein MKP-144

1Mark et al. Clin Cancer Res. 2003;9:1136-1144; 2Mitsiades et al. Blood. 2003;101:2377-2380; 3Hideshima et al. Blood. 2003;101:1530-1534; 4Small et al. Mol. Pharmacol. 2004;66:1478-1490.

CAELYX in relapsed/refractory MMCAELYX in relapsed/refractory MM

No ptsNo pts

2222

44

6262

5050

5050

303303

1818

2828

2323

4444

2020

2525

AutorAutor

Orlowski Orlowski (Blood 05)(Blood 05)

ChariChari (ASH 05) (ASH 05)

BazBaz (Ann Oncol 06) (Ann Oncol 06)

OffidaniOffidani (Haematologica 06) (Haematologica 06)

Hussein Hussein (Mayo Clin Proc 06)(Mayo Clin Proc 06)

OrlowskiOrlowski (JCO 07) (JCO 07)

Jakubowiak Jakubowiak (ASH 07)(ASH 07)

Palumbo Palumbo (Ann Oncol 08)(Ann Oncol 08)

Chanan-KhanChanan-Khan (Leuk Lymph 09) (Leuk Lymph 09)

OffidaniOffidani (SIE 09) (SIE 09)

WatermanWaterman (ASCO 09) (ASCO 09)

Gozzetti (SIE 09)Gozzetti (SIE 09)

Study phaseStudy phase

I/III/II

I/III/II

IIII

II II

IIII

III III

IIII

IIII

IIII

IIII

RetrospRetrosp

IIII

RegimenRegimen

B-PLDB-PLD

MBDoxil MBDoxil

DVd-RDVd-R

ThaDDThaDD

DVd-TDVd-T

V-Doxil V-Doxil vsvs V V

VDDVDD

PADoxilPADoxil

VDTVDT

ThaDD-VThaDD-V

reduced DVDreduced DVD

B-PLD-DB-PLD-D

649649

CAELYX in newly diagnosed MMCAELYX in newly diagnosed MM

AutorAutor

Dimopoulos (Ann Oncol 03)Dimopoulos (Ann Oncol 03)

HusseinHussein (Mayo Clin Proc 06) (Mayo Clin Proc 06)

OffidaniOffidani (Blood 06) (Blood 06)

RifkinRifkin (Cancer 06) (Cancer 06)

ZervasZervas (Ann Oncol 07) (Ann Oncol 07)

PalumboPalumbo (JCO 09) (JCO 09)

JakubowiakJakubowiak (JCO 09) (JCO 09)

BazBaz (ASCO 09) (ASCO 09)

Chanan-Khan Chanan-Khan (ASH 09)(ASH 09)

JakubowiakJakubowiak (ASH 09) (ASH 09)

Study phaseStudy phase

IIIIII

IIII

IIII

III III

IIIIII

IIII

IIII

II II

IIII

I/III/II

RegimenRegimen

VAD bolus VAD bolus vsvs VAD doxil VAD doxil

DVd-TDVd-T

ThaDDThaDD

DVd vs VAdDVd vs VAd

VADdoxil VADdoxil vsvs T-VADdoxil T-VADdoxil

PAD-Mel100PAD-Mel100

VDDVDD

RDDRDD

VDTVDT

R-VDDR-VDD

No ptsNo pts

132 132

5252

5050

9797

117117

102102

4040

31 31

4040

6868

729729

Caelyx + new-drugsCaelyx + new-drugs nel MM nel MM

all’esordioall’esordio

Caelyx 40 mg/mCaelyx 40 mg/m2 2

every 28 daysevery 28 days

Interferon-a 3 MU x 3/weekInterferon-a 3 MU x 3/weekDesametasone 20 mg x 4 days/monthsDesametasone 20 mg x 4 days/months

ThaDD regimen (2003)ThaDD regimen (2003)

11 22 33 44 55 66 77 9988 11111010 1212

Dexamethasone 40 Dexamethasone 40 mg/daymg/day

Dexamethasone 40 Dexamethasone 40 mg/daymg/day

Thalidomide 100 mg day continuously

R

Thalidomide 100 mg/dayThalidomide 100 mg/dayDesametasone 20 mg x 4 days/monthsDesametasone 20 mg x 4 days/months

Response Response ≥ MR≥ MR

Caratteristiche dei 100 pazienti all’esordio Caratteristiche dei 100 pazienti all’esordio

CaratteristicheCaratteristiche

EtàEtà

ISS II-IIIISS II-III

PS (WHO)PS (WHO) ≥ 2≥ 2

Insuff. renaleInsuff. renale

2-microglobulina2-microglobulina

3.5 mg/dl3.5 mg/dl

PCR > range normalePCR > range normale

Cariotipo sfavorevoleCariotipo sfavorevole

Masse extramidollariMasse extramidollari

NN

7878

3333

2323

5656

3535

2525

88

Mediana (range)Mediana (range)

7272 (45-91)(45-91)

3.8 (0.4-30)3.8 (0.4-30)

Risposta esordio Risposta esordio

≥ ≥ PR =PR = 93% 93%

≥ ≥ VGPR =VGPR = 67% 67%

CR+nCR =CR+nCR = 38% 38%

Risposta dopo 6 cicliRisposta dopo 6 cicli

CRCR

nCRnCR

VGPRVGPR

PRPR

RMRM

ProgressioneProgressione

DecessoDecesso

TotaleTotale

N°N°

2929

99

2929

2727

22

11

33

100100

Progression free survival and responseProgression free survival and response

CR: median = 43 mCR: median = 43 m

nCR+VGPR: median = 32 mnCR+VGPR: median = 32 m

PR: median = 16 mPR: median = 16 m

CR CR vvs s nCR+VGPR+PR:nCR+VGPR+PR:Median PFS = Median PFS = 43 43 vsvs 22 22 monthsmonths

5-yrs= 5-yrs= 31%31% vsvs 9%9%

p= 0.031p= 0.031

Progression free survival and responseProgression free survival and response

Overall survival Overall survival

Median OS = Median OS = 56 months56 months

3 yrs OS =3 yrs OS = 69% 69%

5 yrs OS =5 yrs OS = 43% 43%

ThaDD: side effectsThaDD: side effects

TipoTipo

StipsiStipsiAsteniaAsteniaEdemaEdemaRash cutaneoRash cutaneoNeuropatiaNeuropatiaTVP/EPTVP/EPInfezioniInfezioniPPEPPEMucosite oraleMucosite oraleEventi cardiaci ischemiciEventi cardiaci ischemici

NeutropeniaNeutropeniaPiastrinopeniaPiastrinopenia

Grado 3Grado 3

7 7 77442277

11111212331111

7700

Grado 4Grado 4

00000000002244111122

1111

ThaDD: complianceThaDD: compliance

Interruzione Desametasone= 1Interruzione Desametasone= 1Miopatia severaMiopatia severa

Interruzione Caelyx= 1Interruzione Caelyx= 1PPEPPE

Interruzione protocollo= 8Interruzione protocollo= 8

Eventi cardiaci ischemici= 3Eventi cardiaci ischemici= 3

EP= 2EP= 2

Shock settico= 1Shock settico= 1

Mucosite severa= 1Mucosite severa= 1

Scompenso metabolico +FA= 1Scompenso metabolico +FA= 1

Interruzione Thal= 12Rash cutaneo= 2

Neuropatia= 7

TVP= 1

Tremore= 1

Stipsi= 1

Risk of withdrawal from protocolRisk of withdrawal from protocol

10% 10%

ThaDDThaDD

≥ ≥ PR = 93%PR = 93%

≥ ≥ VGPR = 62%VGPR = 62%

CR+nCR = 36%CR+nCR = 36%

median PFS= 28 months

ThaDD

median PFS= 25 months

PFS: ThaDD PFS: ThaDD vsvs DVd-T DVd-T

ThaDDThaDD

≥ ≥ PR = 93%PR = 93%

≥ ≥ VGPR = 62%VGPR = 62%

CR+nCR = 36%CR+nCR = 36%

median PFS= 25 months2 yrs PFS= 54%

ThaDD

Median age= 64.5 yrsMedian age= 64.5 yrs Median age= 72 yrsMedian age= 72 yrs

2 yrs PFS= 59%

PFS: ThaDD PFS: ThaDD vsvs T-VADoxil T-VADoxil

Median age= 64.5 yrsMedian age= 64.5 yrs Median age= 72 yrsMedian age= 72 yrs

4 yrs OS= 68%

4 yrs OS= 58%

OS: ThaDD OS: ThaDD vsvs T-VADoxil T-VADoxil

ThaDD

Side effects: ThaDD Side effects: ThaDD vsvs T-VADoxil T-VADoxil vsvs DVd-T DVd-T

ThaDDThaDDNeuropatia grado 3= 2.5%Neuropatia grado 3= 2.5%

Neutropenia grado 3-4= 5.5%Neutropenia grado 3-4= 5.5%Infezioni gravi= 12.5%Infezioni gravi= 12.5%

DVT= 12.5%DVT= 12.5%PPE severe= 3.5% PPE severe= 3.5%

Confronto regimi MM dell’anzianoConfronto regimi MM dell’anziano

ThaDD ThaDD (Offidani)(Offidani)

100100

7272

2828

2626

5454

8383

3131

1212

MPT MPT (Palumbo)(Palumbo)

129129

7272

2020

1616

5454

8383

3939

1616

N pazientiN pazienti

Età mediana (anni)Età mediana (anni)

>75 anni (%)>75 anni (%)

CRCR

2-yrs PFS (%)2-yrs PFS (%)

2 yrs OS (%)2 yrs OS (%)

Tox non-ematologicaTox non-ematologica

Tox ematologicaTox ematologica

MPT MPT (Facon)(Facon)

125125

7070

00

1313

6161

8585

3333

4848

VMPVMP(San Miguel)(San Miguel)

344344

7171

3131

3535

NANA

82.582.5

4646

40 40

MPRMPR(Palumbo)(Palumbo)

5454

7171

66

2424

6161

9090

3030

6868

VDDVDDVelcade 1.3 mg/sm gg 1, 4, 8, 11Velcade 1.3 mg/sm gg 1, 4, 8, 11Doxil 30 mg/sm gg 4Doxil 30 mg/sm gg 4Desametasone 20 mg gg 1, 2, 4, 5, 8, 9, 11, 12Desametasone 20 mg gg 1, 2, 4, 5, 8, 9, 11, 1240 patients (median age 61, range 38-83)40 patients (median age 61, range 38-83)

Jakubowiak AJ, JCO 2009Jakubowiak AJ, JCO 2009

Toxicity (grade 3-4)Toxicity (grade 3-4)

Neutropenia = 10%Neutropenia = 10%

Infectious = 7.5%Infectious = 7.5%

Neuropathy = 10%Neuropathy = 10%

DVT/PE = 10%DVT/PE = 10%

PPE = 2.5%PPE = 2.5%

Median follow-up = 24 mesiMedian follow-up = 24 mesi

Jakubowiak AJ, JCO 2009Jakubowiak AJ, JCO 2009

Phase II trial of VDT in up-front MMPhase II trial of VDT in up-front MMVDTVDTVelcade 1.3 mg/sm gg 1, 4, 15, 18Velcade 1.3 mg/sm gg 1, 4, 15, 18Doxil 20 mg/sm gg 1 e 15Doxil 20 mg/sm gg 1 e 15Thalidomide 200 mg/dieThalidomide 200 mg/die

40 patients (median age 60.5, range 40-80)40 patients (median age 60.5, range 40-80)

Sher T et al, , ASH 2009Sher T et al, , ASH 2009

ResponseResponse

ORR = 79%ORR = 79%

CR/nCR =38%CR/nCR =38%

Toxicity (grade 3-4)Toxicity (grade 3-4)

Neutropenia = 25%Neutropenia = 25%

Pneumonia = 20%Pneumonia = 20%

Pleural effusion = 10%Pleural effusion = 10%

Thromboembolism= 4%Thromboembolism= 4%

Congestive heart failure = 5%Congestive heart failure = 5%

Neuropathy (Neuropathy ( 2) = 20% 2) = 20%

Palmar plantar erythrodysesthesia = 15%Palmar plantar erythrodysesthesia = 15%

OutcomeOutcome

1-yr PFS = 81%1-yr PFS = 81%

1-yr OS = 97%1-yr OS = 97%

Phase II trial of RDD in up-front MMPhase II trial of RDD in up-front MM

RDDRDDRevlimid 25 mg days 1-21Revlimid 25 mg days 1-21Doxil 40 mg/sm day 1 Doxil 40 mg/sm day 1 (amended to 30 mg/sm due to neutropenia)(amended to 30 mg/sm due to neutropenia)

Dexamethasone 40 mg days 1-4Dexamethasone 40 mg days 1-4

31 patients (median age 64, range 41-82)31 patients (median age 64, range 41-82)

Baz R, ASCO 2009Baz R, ASCO 2009

ResponseResponse

ORR = 80%ORR = 80%

≥ ≥ VGPR = 40%VGPR = 40%

Toxicity (grade 3-4)Toxicity (grade 3-4)

Neutropenia = 48%Neutropenia = 48%

Infectious = 20%Infectious = 20%

Fatigue = 21%Fatigue = 21%

DVT = 10%DVT = 10%

Phase I/II trial of RVDD in up-front MMPhase I/II trial of RVDD in up-front MMRVDDRVDDRevlimid 15-25 mg days 1-14Revlimid 15-25 mg days 1-14Velcade 1.3 mg/sm days 1, 4 , 8, 11 Velcade 1.3 mg/sm days 1, 4 , 8, 11 Doxil 20-30 mg/sm day 4Doxil 20-30 mg/sm day 4Dexamethasone 20/10 mg (cycles 1-4/5-8; on day and day after Velcade) Dexamethasone 20/10 mg (cycles 1-4/5-8; on day and day after Velcade)

68 patients (median age 61)68 patients (median age 61)

Jakuboviak AJ, ASH 2009Jakuboviak AJ, ASH 2009

ResponseResponse

ORR = 96%ORR = 96%

≥ ≥ VGPR = 58%VGPR = 58%

≥ ≥ nCR = 30%nCR = 30%

Toxicity (grade 3-4)Toxicity (grade 3-4)

Neutropenia = 18%Neutropenia = 18%

Thrombocytopenia = 7%Thrombocytopenia = 7%

Infectious = 16%Infectious = 16%

Peripheral neuropathy = 4%Peripheral neuropathy = 4%

DVT = 2%DVT = 2%

PAD-MEL100-LP-LPAD-MEL100-LP-L

Palumbo A, JCO in pressPalumbo A, JCO in press

Velcade 1.3 mg/mq gg 1, 4, 15, 18Velcade 1.3 mg/mq gg 1, 4, 15, 18Doxil 30 mg/mq gg 4Doxil 30 mg/mq gg 4Desametasone 40 mg gg 1-4, 8-11, 15-18 ciclo 1 e gg 1-4 cicli 2-4.Desametasone 40 mg gg 1-4, 8-11, 15-18 ciclo 1 e gg 1-4 cicli 2-4.

CTX (3 g/mq) + G-CSFCTX (3 g/mq) + G-CSFDoppio Mel 100 mg/mqDoppio Mel 100 mg/mq

Lenalidomide 25 mg gg 1-21+ PDN 50 mg gg alterniLenalidomide 25 mg gg 1-21+ PDN 50 mg gg alterni

Len 10 mg gg 1-21 ogni 28 ggLen 10 mg gg 1-21 ogni 28 gg

InduzioneInduzione

ASCTASCT

ConsolidamentoConsolidamento

MantenimentoMantenimento

102 patients (median age 67, range 65-102 patients (median age 67, range 65-75)75)

4 PAD4 PAD

PR = PR = 96%96%

VGPR =VGPR = 60% 60%

CR =CR = 13% 13%

Tandem MEL100Tandem MEL100

PR = PR = 99%99%

VGPR =VGPR = 82% 82%

CR =CR = 38.5% 38.5%

PR = PR = 100%100%

VGPR =VGPR = 86% 86%

CR =CR = 66% 66%

Cons-Mant LP-LCons-Mant LP-L

Grado 3-4 tossicità ematologica = Grado 3-4 tossicità ematologica = 27%27%

Grado 3-4 neuropatia periferica =Grado 3-4 neuropatia periferica = 16% 16%

Grado 3-4 infezioni =Grado 3-4 infezioni = 10% 10%

Caelyx: 3-4 drug combinationsCaelyx: 3-4 drug combinations

PADPAD

PalumboPalumbo

102102

6767

9696

6060

7878

8484

2727

2626

VDDVDD

JakubowiakJakubowiak

4040

6161

8585

57.557.5

8080

9292

1010

37.537.5

VDTVDT

Chanan-KanChanan-Kan

4040

60.560.5

79.479.4

nana

81 (1-yr)81 (1-yr)

97 (1-yr)97 (1-yr)

2525

4444

RDDRDD

BazBaz

3131

6464

8080

4040

nana

nana

4848

3030

ThaDDThaDD

OffidaniOffidani

100100

7272

9393

6767

5454

8383

88

3636

RVDDRVDD

JakubowiakJakubowiak

6868

6161

9696

5858

nana

nana

1818

2222

No of ptsNo of pts

Median ageMedian age

ORR (%)ORR (%)

≥≥VGPRVGPR (%) (%)

2 yrs PFS (%)2 yrs PFS (%)

2-yrs2-yrs OS (%) OS (%)

Max haemat toxicity Max haemat toxicity

Non-haemat toxicityNon-haemat toxicity

Caelyx + new-drugs nel MM Caelyx + new-drugs nel MM recidivato/refrattariorecidivato/refrattario

Bortezomib + CAELYX Bortezomib + CAELYX vsvs Bortezomib Bortezomib Monotherapy: Study DesignMonotherapy: Study Design

Bortezomib 1.3 mg/mBortezomib 1.3 mg/m22 days 1, 4, days 1, 4, 8, 11 every 21 days8, 11 every 21 days

Bortezomib as above + Bortezomib as above +

CAELYX 30 mg/mCAELYX 30 mg/m22 on day 4 on day 4

Study DesignStudy DesignRelapsed or refractory MMRelapsed or refractory MM

Phase III, multicenter (123 Phase III, multicenter (123 participating centers)participating centers)

EligibilityEligibility2+ lines of therapy2+ lines of therapy

Bortezomib-naïveBortezomib-naïve

ECOG 0-1ECOG 0-1

RANDOMIZATION

N = 646N = 646

Treat until progression, unacceptable Treat until progression, unacceptable toxicity or max. of 8 cycles (unless disease toxicity or max. of 8 cycles (unless disease still responding)still responding)

Orlowski et al. J Clin Oncol. 2007;25:3892-3901.

Primary endpoint: TTPPrimary endpoint: TTP

Secondary: OS, ORR, safetySecondary: OS, ORR, safety

StratifyStratifyββ22microglobulin (≤ 2.5, microglobulin (≤ 2.5,

> 2.5 but ≤ 5.5, > 5.5)> 2.5 but ≤ 5.5, > 5.5)

Response vs progression to prior treatmentResponse vs progression to prior treatment

Response RateResponse Rate

BortezomibBortezomib(n = 322) (n = 322)

CAELYX + CAELYX + BortezomibBortezomib(n = 324) (n = 324)

P-valueP-value

Total Total (CR + nCR + PR)(CR + nCR + PR)

41%41% 44%44% .43.43

CR CR nCRnCR

2%2%8%8%

4%4%9%9%

PRPR 39%39% 40%40%

CR + VGPR CR + VGPR 19%19% 27%27%.0157.0157

Duration of Duration of responseresponse

7.0 months7.0 months(5.9-8.3)(5.9-8.3)

10.2 months10.2 months(10.2-12.9)(10.2-12.9)

.0008.0008

Orlowski et al. J Clin Oncol. 2007;25:3892-3901.

Time-to-Progression

Orlowski et al. J Clin Oncol. 2007;25:3892-3901

Selected Adverse Events of Interest

Bortezomib Bortezomib (n = 318)(n = 318)

CAELYX + CAELYX + Bortezomib Bortezomib

(n = 318)(n = 318)

TotalTotalGrade Grade

3/43/4TotalTotal Grade 3/4Grade 3/4

Peripheral neuropathyPeripheral neuropathy 39%39% 9%9% 35%35% 4%4%

Febrile neutropeniaFebrile neutropenia 2%2% 2%2% 3%3% 3%3%

Bleeding/hemorrhageBleeding/hemorrhage 9%9% 1%1% 14%14% 4%4%

Thromboembolic Thromboembolic events events

1%1% 1%1% 1%1% 1%1%

Cardiac eventsCardiac events 7%7% 3%3% 10%10% 2%2%

AlopeciaAlopecia 1%1% 00 2%2% 00

Orlowski et al. J Clin Oncol. 2007;25:3892-3901

Risposta terapiaRisposta terapia

≥ ≥ VGPR= 36% VGPR= 36% vsvs 15% (p= 0.018) 15% (p= 0.018)

≥ ≥ nCR= 30% nCR= 30% vsvs 10.5% (p= 0.022) 10.5% (p= 0.022)

European Journal of Hematology, 2007European Journal of Hematology, 2007

2-yrs EFS: 44% vs 23%

Dex: 20 mg/d

Thal: 100 mg/d (ameneded to 50 mg)

Bort: 1.3 mg/m2 (amended to 1, 4, 11)

Doxil: 30 mg/m2

1 2 4 5 8 9 11 12 14 28

Thalidomide

Day

D D D D

BB BB BB BB

D

INDUCTIONINDUCTION

CONSOLIDATIONCONSOLIDATION

1 2 4 5 8 9 11 12

D D D D

BB BB BB BB

20 mg/d (amended to 1,2 and 8,9)

1 mg/m2 (amended to 1 and 8)

Day

1 2 3 4 28

D

Thalidomide 100 mg/d

20 mg/d

6 ALTERNATING 6 ALTERNATING CYCLES EVERY CYCLES EVERY

28 DAYS28 DAYS

MAINTENANCEMAINTENANCE

Thalidomide 100 mg/d (amended to 50 mg/d)

ThaDD-VThaDD-V

My-VTDMy-VTD

Thalidomide 100 mg/dieThalidomide 100 mg/die

Desametasone 24 mg giorni 1,2 - 4,5 - 8,9 - 11,12Desametasone 24 mg giorni 1,2 - 4,5 - 8,9 - 11,12

Myocet 30-50 mg/mMyocet 30-50 mg/m22 giorno 4 giorno 4

Velcade 1.0 mg/mVelcade 1.0 mg/m22 giorni 1, 4, 8, 11 giorni 1, 4, 8, 11

Ciolli et al , BJH 2008Ciolli et al , BJH 2008

ThaDD-VThaDD-V

Thalidomide 100 mg/dieThalidomide 100 mg/die

Desametasone 20 mg giorni 1,2 - 4,5 - 8,9 - 11,12Desametasone 20 mg giorni 1,2 - 4,5 - 8,9 - 11,12

Caelyx 30 mg/mCaelyx 30 mg/m22 giorno 4 giorno 4

Velcade 1.3 mg/mVelcade 1.3 mg/m22 giorni 1, 4, 8, 11 giorni 1, 4, 8, 11

Offidani et al, EHA 2009Offidani et al, EHA 2009

ThaDD-V ThaDD-V vsvs My-VTD: caratteristiche pazienti My-VTD: caratteristiche pazienti

ThaDD-VThaDD-V

(44 pts)(44 pts)

63.5 (31-83)63.5 (31-83)

31 (74)31 (74)

6 (14)6 (14)

13 (29)13 (29)

22 (1-6) (1-6)

1919 (43)(43)

7 (16)7 (16)

20 20 (48)(48)

CaratteristicheCaratteristiche

Età medianaEtà mediana

ISS II-IIIISS II-III

Insuff. renaleInsuff. renale

Citogenetica sfavorevoleCitogenetica sfavorevole

Linee terapia precedenteLinee terapia precedente

Precedente thalidomidePrecedente thalidomide

Precedente bortezomibPrecedente bortezomib

Precedente trapiantoPrecedente trapianto

My-VTDMy-VTD

(42 pts)(42 pts)

63 (35-81)63 (35-81)

32 (76)32 (76)

4 (9.5)4 (9.5)

nana

33 (1-6) (1-6)

27 27 (64)(64)

6 (14)6 (14)

10 10 (24)(24)

ThaDD-VThaDD-V(44 pts)(44 pts)

8686

7777

4545

3030

5454

44 44

6363

OutcomesOutcomes

≥ ≥ PRPR

≥ ≥ VGPRVGPR

≥ ≥ nCRnCR

Follow-up mediano (mesi)Follow-up mediano (mesi)

2-yrs TTP (%)2-yrs TTP (%)

2-yrs PFS (%)2-yrs PFS (%)

2-yrs OS (%)2-yrs OS (%)

My-VTDMy-VTD(42 pts)(42 pts)

7373

nana

5252

1818

3030

2020

6666

ThaDD-V ThaDD-V vsvs My-VTD: outcomes My-VTD: outcomes

ThaDD-V ThaDD-V vsvs My-VTD: median PFS My-VTD: median PFS

PFS=28 mesi

ThaDD-VThaDD-V My-VTDMy-VTD

PFS=19 mesi

ThaDD-V ThaDD-V vsvs My-VTD: eventi avversi grado 3-4 My-VTD: eventi avversi grado 3-4

Eventi avversiEventi avversi

NeutropeniaNeutropenia

PiastrinopeniaPiastrinopenia

InfezioniInfezioni

AlopeciaAlopecia

EmorragiaEmorragia

TVPTVP

NeuropatiaNeuropatia

PPEPPE

Eventi cardiaciEventi cardiaci

Totale eventiTotale eventi

ThaDD-VThaDD-V(44 pts)(44 pts)

4 (9)4 (9)

7 (16)7 (16)

7 (15)7 (15)

00

00

2 (4.5) 2 (4.5)

5 5 (11)(11)

00

00

2525

My-VTDMy-VTD(42 pts)(42 pts)

10 10 (24)(24)

12 (29)12 (29)

5 5 (12)*(12)*

7 (17)7 (17)

2 (5)2 (5)

1 (2)1 (2)

1 1 (2)(2)

00

00

3838

* 10 (24%) grado 2 e 2 (5%) grado 3 episodi di neutropenia febbrile

Phase I trial of vorinostat in combination with Phase I trial of vorinostat in combination with pegylated liposomal doxorubicin and bortezomib in pegylated liposomal doxorubicin and bortezomib in

patients with relapsed/refractory MMpatients with relapsed/refractory MM

Velcade 1.3 mg/sm days 1, 4 , 8, 11 Velcade 1.3 mg/sm days 1, 4 , 8, 11

Doxil 30 mg/sm day 4Doxil 30 mg/sm day 4

Vorinostat 200Vorinostat 200400 mg on day 4 through 11 of a 3-week cycle400 mg on day 4 through 11 of a 3-week cycle

9 patients (median age 56 yrs, median time from diagnosis = 66 months)9 patients (median age 56 yrs, median time from diagnosis = 66 months)

• 6/9 prior bortezomib (3 refractory)6/9 prior bortezomib (3 refractory)

• 7/9 orior anthracyclines 7/9 orior anthracyclines

• 9/9 prior corticosteroids9/9 prior corticosteroids

• 7/9 prior stem cell transplantation7/9 prior stem cell transplantation

7 evaluable patients: 1 CR, 1 VGPR, 4 PR, 1 non responder7 evaluable patients: 1 CR, 1 VGPR, 4 PR, 1 non responder

fatigue= 44%, constipation= 67%, diarrhea= 67%, nausea= 56%, fatigue= 44%, constipation= 67%, diarrhea= 67%, nausea= 56%, vomiting = 33%, peripheral neuropathy= 56%, neutropenia= 44%, vomiting = 33%, peripheral neuropathy= 56%, neutropenia= 44%, thrombocytopenia= 67%thrombocytopenia= 67%

Voorhees P et al, , ASH 2009Voorhees P et al, , ASH 2009

Caelyx quarta novità nel MMCaelyx quarta novità nel MM

Elevati livelli di risposte di ottima qualità Elevati livelli di risposte di ottima qualità

Caelyx determina una modesta tossicità ematologicaCaelyx determina una modesta tossicità ematologica

Tossicità extraematologica contenuta e gestibileTossicità extraematologica contenuta e gestibile

Ottimo partner per ulteriori studi di fase IIIOttimo partner per ulteriori studi di fase III

Considerazioni finaliConsiderazioni finali