Esperienza clinica con le antracicline liposomiali nel MM Massimo Offidani Clinica di Ematologia Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona

Effect of single drug doxorubicin in MM 9 rel/ref MM pts: 1 PR and 1 MR (Alberts DS et al: Cancer Chem Rep, 1975) Review of literature rel/ref MM: 5% PR (Rodjer S et al: Haemat J, 2000) Effect of doxorubicin combinations in MM VAD: PR=50-65%, VGPR=15%, CR/nCR=4-8%

Anthracyclines in Multiple Myeloma Doxorubicin is one of the most potent antibiotics used in tumor chemotherapy Longer exposure to higher concentrations results in higher plasma cell kill Short half life have negative impact on the administration modality Total cumulative effect limits its use in chronic disease processes

Rationale for Pegylated Liposomal Doxorubicin in MM Increased angiogenesis in BM of MM patients Longer plasma half life Possible more effective against MDR positive cells Improved safety profile compared to free doxorubicin Outpatient regimen

Why CAELYX in Multiple Myeloma? CAELYX has a favorable safety profile Phase III DVd vs VAd RR, PFS, OS similar Significantly less neutropenia (10 vs 24%) Alopecia (20 vs 44%) Less supportive care (CVA, GFs) DVd regimen decreased angiogenic activity in BM Need for modifying anthracycline-based regimens with the addition of new-drugs Thalidomide, Lenalidomide Bortezomib Rifkin et al. Cancer. 2006;106:848-858 Hussein et al. Clin Lymphoma Myeloma. 2007;7(suppl 4):S145-S149

Preclinical rationale for Pegylated Liposomal Doxorubicin + IMiDs in MM Different but complementary mechanism of action Both antiangiogenic Both cytotoxic effect with different mechanism IMiDs target microenvironment IMiDs exert immune activation effect Nonoverlapping toxicities

Preclinical Rationale for Combining CAELYX + Bortezomib Additive or synergistic effects are seen in both in vitro1,2,3 and in vivo4 model systems Interactions occur through multiple pathways to enhance anti-tumor efficacy Bortezomib abrogates anthracycline resistance NF-kB1,2, Bcl-2, P-glycoprotein, DNA damage repair3 Anthracyclines abrogate bortezomib resistance Suppression of stress response protein MKP-14 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 MM Autor Orlowski (Blood 05) Chari (ASH 05) Baz (Ann Oncol 06) Offidani (Haematologica 06) Hussein (Mayo Clin Proc 06) Orlowski (JCO 07) Jakubowiak (ASH 07) Palumbo (Ann Oncol 08) Chanan-Khan (Leuk Lymph 09) Offidani (SIE 09) Waterman (ASCO 09) Gozzetti (SIE 09) Study phase I/II II III Retrosp Regimen B-PLD MBDoxil DVd-R ThaDD DVd-T V-Doxil vs V VDD PADoxil VDT ThaDD-V reduced DVD B-PLD-D No pts 22 4 62 50 303 18 28 23 44 20 25 649

CAELYX in newly diagnosed MM VADdoxil vs T-VADdoxil Autor Dimopoulos (Ann Oncol 03) Hussein (Mayo Clin Proc 06) Offidani (Blood 06) Rifkin (Cancer 06) Zervas (Ann Oncol 07) Palumbo (JCO 09) Jakubowiak (JCO 09) Baz (ASCO 09) Chanan-Khan (ASH 09) Jakubowiak (ASH 09) Study phase III II I/II Regimen VAD bolus vs VAD doxil DVd-T ThaDD DVd vs VAd VADdoxil vs T-VADdoxil PAD-Mel100 VDD RDD VDT R-VDD No pts 132 52 50 97 117 102 40 31 68 729

Caelyx + new-drugs nel MM all’esordio

ThaDD regimen (2003) Caelyx 40 mg/m2 every 28 days 1 2 3 4 5 6 7 8 9 10 11 12 Dexamethasone 40 mg/day Dexamethasone 40 mg/day Thalidomide 100 mg day continuously Response ≥ MR R Thalidomide 100 mg/day Desametasone 20 mg x 4 days/months Interferon-a 3 MU x 3/week Desametasone 20 mg x 4 days/months

Caratteristiche dei 100 pazienti all’esordio Età ISS II-III PS (WHO) ≥ 2 Insuff. renale b2-microglobulina  3.5 mg/dl PCR > range normale Cariotipo sfavorevole Masse extramidollari N 78 33 23 56 35 25 8 Mediana (range) 72 (45-91) 3.8 (0.4-30)

Risposta esordio ≥ PR = 93% ≥ VGPR = 67% CR+nCR = 38% Risposta dopo 6 cicli CR nCR VGPR PR RM Progressione Decesso Totale N° 29 9 27 2 1 3 100 ≥ PR = 93% ≥ VGPR = 67% CR+nCR = 38%

Progression free survival and response CR: median = 43 m nCR+VGPR: median = 32 m PR: median = 16 m

Progression free survival and response CR vs nCR+VGPR+PR: Median PFS = 43 vs 22 months 5-yrs= 31% vs 9% p= 0.031

Overall survival Median OS = 56 months 3 yrs OS = 69% 5 yrs OS = 43%

ThaDD: side effects Tipo Stipsi Astenia Edema Rash cutaneo Neuropatia TVP/EP Infezioni PPE Mucosite orale Eventi cardiaci ischemici Neutropenia Piastrinopenia Grado 3 7 4 2 11 12 3 1 Grado 4 2 4 1

ThaDD: compliance Interruzione protocollo= 8 Interruzione Thal= 12 Eventi cardiaci ischemici= 3 EP= 2 Shock settico= 1 Mucosite severa= 1 Scompenso metabolico +FA= 1 Interruzione Thal= 12 Rash cutaneo= 2 Neuropatia= 7 TVP= 1 Tremore= 1 Stipsi= 1 Interruzione Desametasone= 1 Miopatia severa Interruzione Caelyx= 1 PPE

Risk of withdrawal from protocol 10%

ThaDD ≥ PR = 93% ≥ VGPR = 62% CR+nCR = 36%

PFS: ThaDD vs DVd-T ThaDD median PFS= 25 months median PFS= 28 months

ThaDD ≥ PR = 93% ≥ VGPR = 62% CR+nCR = 36%

PFS: ThaDD vs T-VADoxil median PFS= 25 months 2 yrs PFS= 54% 2 yrs PFS= 59% Median age= 64.5 yrs Median age= 72 yrs

OS: ThaDD vs T-VADoxil ThaDD Median age= 64.5 yrs Median age= 72 yrs 4 yrs OS= 68% 4 yrs OS= 58% Median age= 64.5 yrs Median age= 72 yrs

Side effects: ThaDD vs T-VADoxil vs DVd-T Neuropatia grado 3= 2.5% Neutropenia grado 3-4= 5.5% Infezioni gravi= 12.5% DVT= 12.5% PPE severe= 3.5%

Confronto regimi MM dell’anziano N pazienti Età mediana (anni) >75 anni (%) CR 2-yrs PFS (%) 2 yrs OS (%) Tox non-ematologica Tox ematologica MPT (Palumbo) 129 72 20 16 54 83 39 MPT (Facon) 125 70 13 61 85 33 48 MPR (Palumbo) 54 71 6 24 61 90 30 68 VMP (San Miguel) 344 71 31 35 NA 82.5 46 40 ThaDD (Offidani) 100 72 28 26 54 83 31 12

Toxicity (grade 3-4) Neutropenia = 10% Infectious = 7.5% VDD Velcade 1.3 mg/sm gg 1, 4, 8, 11 Doxil 30 mg/sm gg 4 Desametasone 20 mg gg 1, 2, 4, 5, 8, 9, 11, 12 40 patients (median age 61, range 38-83) Toxicity (grade 3-4) Neutropenia = 10% Infectious = 7.5% Neuropathy = 10% DVT/PE = 10% PPE = 2.5% Jakubowiak AJ, JCO 2009

Median follow-up = 24 mesi Jakubowiak AJ, JCO 2009

Phase II trial of VDT in up-front MM Velcade 1.3 mg/sm gg 1, 4, 15, 18 Doxil 20 mg/sm gg 1 e 15 Thalidomide 200 mg/die 40 patients (median age 60.5, range 40-80) Response ORR = 79% CR/nCR =38% Toxicity (grade 3-4) Neutropenia = 25% Pneumonia = 20% Pleural effusion = 10% Thromboembolism= 4% Congestive heart failure = 5% Neuropathy ( 2) = 20% Palmar plantar erythrodysesthesia = 15% Outcome 1-yr PFS = 81% 1-yr OS = 97% Sher T et al, , ASH 2009

Phase II trial of RDD in up-front MM Revlimid 25 mg days 1-21 Doxil 40 mg/sm day 1 (amended to 30 mg/sm due to neutropenia) Dexamethasone 40 mg days 1-4 31 patients (median age 64, range 41-82) Response ORR = 80% ≥ VGPR = 40% Toxicity (grade 3-4) Neutropenia = 48% Infectious = 20% Fatigue = 21% DVT = 10% Baz R, ASCO 2009

Phase I/II trial of RVDD in up-front MM Peripheral neuropathy = 4% Revlimid 15-25 mg days 1-14 Velcade 1.3 mg/sm days 1, 4 , 8, 11 Doxil 20-30 mg/sm day 4 Dexamethasone 20/10 mg (cycles 1-4/5-8; on day and day after Velcade) 68 patients (median age 61) Response ORR = 96% ≥ VGPR = 58% ≥ nCR = 30% Toxicity (grade 3-4) Neutropenia = 18% Thrombocytopenia = 7% Infectious = 16% Peripheral neuropathy = 4% DVT = 2% Jakuboviak AJ, ASH 2009

PAD-MEL100-LP-L Velcade 1.3 mg/mq gg 1, 4, 15, 18 Doxil 30 mg/mq gg 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-CSF Doppio Mel 100 mg/mq Lenalidomide 25 mg gg 1-21+ PDN 50 mg gg alterni Len 10 mg gg 1-21 ogni 28 gg Induzione ASCT Consolidamento Mantenimento 102 patients (median age 67, range 65-75) 4 PAD PR = 96% VGPR = 60% CR = 13% Tandem MEL100 PR = 99% VGPR = 82% CR = 38.5% PR = 100% VGPR = 86% CR = 66% Cons-Mant LP-L Grado 3-4 tossicità ematologica = 27% Grado 3-4 neuropatia periferica = 16% Grado 3-4 infezioni = 10% Palumbo A, JCO in press

Caelyx: 3-4 drug combinations No of pts Median age ORR (%) ≥VGPR (%) 2 yrs PFS (%) 2-yrs OS (%) Max haemat toxicity Non-haemat toxicity VDD Jakubowiak 40 61 85 57.5 80 92 10 37.5 PAD Palumbo 102 67 96 60 78 84 27 26 VDT Chanan-Kan 40 60.5 79.4 na 81 (1-yr) 97 (1-yr) 25 44 RDD Baz 31 64 80 40 na 48 30 ThaDD Offidani 100 72 93 67 54 83 8 36 RVDD Jakubowiak 68 61 96 58 na 18 22

Caelyx + new-drugs nel MM recidivato/refrattario

Bortezomib + CAELYX vs Bortezomib Monotherapy: Study Design Relapsed or refractory MM Phase III, multicenter (123 participating centers) Eligibility 2+ lines of therapy Bortezomib-naïve ECOG 0-1 N = 646 R A N D O M I Z T Bortezomib 1.3 mg/m2 days 1, 4, 8, 11 every 21 days Treat until progression, unacceptable toxicity or max. of 8 cycles (unless disease still responding) Bortezomib as above + CAELYX 30 mg/m2 on day 4 Stratify β2microglobulin (≤ 2.5, > 2.5 but ≤ 5.5, > 5.5) Response vs progression to prior treatment Primary endpoint: TTP Secondary: OS, ORR, safety Orlowski et al. J Clin Oncol. 2007;25:3892-3901.

Response Rate Bortezomib (n = 322) CAELYX + Bortezomib (n = 324) P-value Total (CR + nCR + PR) 41% 44% .43 CR nCR 2% 8% 4% 9% PR 39% 40% CR + VGPR 19% 27% .0157 Duration of response 7.0 months (5.9-8.3) 10.2 months (10.2-12.9) .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 (n = 318) CAELYX + Bortezomib Total Grade 3/4 Peripheral neuropathy 39% 9% 35% 4% Febrile neutropenia 2% 3% Bleeding/hemorrhage 1% 14% Thromboembolic events Cardiac events 7% 10% Alopecia Orlowski et al. J Clin Oncol. 2007;25:3892-3901

Risposta terapia ≥ VGPR= 36% vs 15% (p= 0.018) ≥ nCR= 30% vs 10.5% (p= 0.022) 2-yrs EFS: 44% vs 23% European Journal of Hematology, 2007

ThaDD-V INDUCTION CONSOLIDATION MAINTENANCE Thalidomide D D D D B B B Day 1 2 4 5 8 9 11 12 14 28 Thalidomide Thal: 100 mg/d (ameneded to 50 mg) Dex: 20 mg/d D D D D B B B B Bort: 1.3 mg/m2 (amended to 1, 4, 11) D Doxil: 30 mg/m2 CONSOLIDATION Day 1 2 4 5 8 9 11 12 20 mg/d (amended to 1,2 and 8,9) D D D D 6 ALTERNATING CYCLES EVERY 28 DAYS B B B B 1 mg/m2 (amended to 1 and 8) 100 mg/d Thalidomide 1 2 3 4 28 20 mg/d D MAINTENANCE Thalidomide 100 mg/d (amended to 50 mg/d)

ThaDD-V My-VTD Thalidomide 100 mg/die Desametasone 20 mg giorni 1,2 - 4,5 - 8,9 - 11,12 Caelyx 30 mg/m2 giorno 4 Velcade 1.3 mg/m2 giorni 1, 4, 8, 11 Offidani et al, EHA 2009 My-VTD Thalidomide 100 mg/die Desametasone 24 mg giorni 1,2 - 4,5 - 8,9 - 11,12 Myocet 30-50 mg/m2 giorno 4 Velcade 1.0 mg/m2 giorni 1, 4, 8, 11 Ciolli et al , BJH 2008

ThaDD-V vs My-VTD: caratteristiche pazienti Età mediana ISS II-III Insuff. renale Citogenetica sfavorevole Linee terapia precedente Precedente thalidomide Precedente bortezomib Precedente trapianto ThaDD-V (44 pts) 63.5 (31-83) 31 (74) 6 (14) 13 (29) 2 (1-6) 19 (43) 7 (16) 20 (48) My-VTD (42 pts) 63 (35-81) 32 (76) 4 (9.5) na 3 (1-6) 27 (64) 6 (14) 10 (24)

ThaDD-V vs My-VTD: outcomes (44 pts) 86 77 45 30 54 44 63 Outcomes ≥ PR ≥ VGPR ≥ nCR Follow-up mediano (mesi) 2-yrs TTP (%) 2-yrs PFS (%) 2-yrs OS (%) My-VTD (42 pts) 73 na 52 18 20 66

ThaDD-V vs My-VTD: median PFS PFS=19 mesi PFS=28 mesi

ThaDD-V vs My-VTD: eventi avversi grado 3-4 (44 pts) 4 (9) 7 (16) 7 (15) 2 (4.5) 5 (11) 25 My-VTD (42 pts) 10 (24) 12 (29) 5 (12)* 7 (17) 2 (5) 1 (2) 38 Eventi avversi Neutropenia Piastrinopenia Infezioni Alopecia Emorragia TVP Neuropatia PPE Eventi cardiaci Totale eventi * 10 (24%) grado 2 e 2 (5%) grado 3 episodi di neutropenia febbrile

Phase I trial of vorinostat in combination with pegylated liposomal doxorubicin and bortezomib in patients with relapsed/refractory MM Velcade 1.3 mg/sm days 1, 4 , 8, 11 Doxil 30 mg/sm day 4 Vorinostat 200400 mg on day 4 through 11 of a 3-week cycle 9 patients (median age 56 yrs, median time from diagnosis = 66 months) 6/9 prior bortezomib (3 refractory) 7/9 orior anthracyclines 9/9 prior corticosteroids 7/9 prior stem cell transplantation 7 evaluable patients: 1 CR, 1 VGPR, 4 PR, 1 non responder fatigue= 44%, constipation= 67%, diarrhea= 67%, nausea= 56%, vomiting = 33%, peripheral neuropathy= 56%, neutropenia= 44%, thrombocytopenia= 67% Voorhees P et al, , ASH 2009

Considerazioni finali Caelyx quarta novità nel MM Elevati livelli di risposte di ottima qualità Caelyx determina una modesta tossicità ematologica Tossicità extraematologica contenuta e gestibile Ottimo partner per ulteriori studi di fase III