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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