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

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Presentazione sul tema: "Esperienza clinica con le antracicline liposomiali nel MM Massimo Offidani Clinica di Ematologia Azienda Ospedaliero-Universitaria Ospedali Riuniti di."— Transcript della presentazione:

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

2 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%

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

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

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

6 Preclinical rationale for Pegylated Liposomal Doxorubicin + IMiDs in MM Different 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

7 Preclinical Rationale for Combining CAELYX + Bortezomib Additive or synergistic effects are seen in both in vitro 1,2,3 and in vivo 4 model systemsAdditive or synergistic effects are seen in both in vitro 1,2,3 and in vivo 4 model systems Interactions occur through multiple pathways to enhance anti-tumor efficacyInteractions occur through multiple pathways to enhance anti-tumor efficacy –Bortezomib abrogates anthracycline resistance NF-kB 1,2, Bcl-2, P-glycoprotein, DNA damage repair 3 NF-kB 1,2, Bcl-2, P-glycoprotein, DNA damage repair 3 –Anthracyclines abrogate bortezomib resistance Suppression of stress response protein MKP-1 4Suppression of stress response protein MKP Mark et al. Clin Cancer Res. 2003;9: ; 2 Mitsiades et al. Blood. 2003;101: ; 3 Hideshima et al. Blood. 2003;101: ; 4 Small et al. Mol. Pharmacol. 2004;66:

8 CAELYX in relapsed/refractory MM No pts 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/III/IIIIIIIIIIIIIIIIIIIRetrospIIRegimenB-PLDMBDoxilDVd-RThaDDDVd-T V-Doxil vs V VDDPADoxilVDTThaDD-V reduced DVD B-PLD-D 649

9 CAELYX in newly diagnosed MM 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 IIIIIIIIIIIIIIIIIIIIII/IIRegimen VAD bolus vs VAD doxil DVd-TThaDD DVd vs VAd VADdoxil vs T-VADdoxil PAD-Mel100VDDRDDVDTR-VDD No pts

10 Caelyx + new-drugs nel MM nel MMallesordio

11 Caelyx 40 mg/m 2 every 28 days Caelyx 40 mg/m 2 every 28 days Interferon-a 3 MU x 3/week Desametasone 20 mg x 4 days/months ThaDD regimen (2003) Dexamethasone 40 mg/day Dexamethasone 40 mg/day Thalidomide 100 mg day continuously R Thalidomide 100 mg/day Desametasone 20 mg x 4 days/months Response MR

12 Caratteristiche dei 100 pazienti allesordio CaratteristicheEtà ISS II-III PS (WHO) 2 Insuff. renale 2-microglobulina 2-microglobulina 3.5 mg/dl 3.5 mg/dl PCR > range normale Cariotipo sfavorevole Masse extramidollari N Mediana (range) 72 (45-91) 3.8 (0.4-30)

13 Risposta esordio PR = 93% PR = 93% VGPR = 67% VGPR = 67% CR+nCR = 38% Risposta dopo 6 cicli CRnCRVGPRPRRMProgressioneDecessoTotaleN°

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

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

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

17 ThaDD: side effects TipoStipsiAsteniaEdema Rash cutaneo NeuropatiaTVP/EPInfezioniPPE Mucosite orale Eventi cardiaci ischemici NeutropeniaPiastrinopenia Grado Grado

18 ThaDD: compliance Interruzione Desametasone= 1 Miopatia severa Interruzione Caelyx= 1 PPE Interruzione protocollo= 8 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

19 Risk of withdrawal from protocol 10%

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

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

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

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

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

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

26 Confronto regimi MM dellanziano ThaDD (Offidani) MPT (Palumbo) N pazienti Età mediana (anni) >75 anni (%) CR 2-yrs PFS (%) 2 yrs OS (%) Tox non-ematologica Tox ematologica MPT (Facon) VMP (San Miguel) NA MPR(Palumbo)

27 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, patients (median age 61, range 38-83) Jakubowiak AJ, JCO 2009 Toxicity (grade 3-4) Neutropenia = 10% Infectious = 7.5% Neuropathy = 10% DVT/PE = 10% PPE = 2.5%

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

29 Phase II trial of VDT in up-front MM VDT 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) Sher T et al,, ASH 2009 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%

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

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

32 PAD-MEL100-LP-L Palumbo A, JCO in press Velcade 1.3 mg/mq gg 1, 4, 15, 18 Doxil 30 mg/mq gg 4 Desametasone 40 mg gg 1-4, 8-11, ciclo 1 e gg 1-4 cicli 2-4. CTX (3 g/mq) + G-CSF Doppio Mel 100 mg/mq Lenalidomide 25 mg gg 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% PR = 96% VGPR = 60% VGPR = 60% CR = 13% Tandem MEL100 PR = 99% PR = 99% VGPR = 82% VGPR = 82% CR = 38.5% PR = 100% PR = 100% VGPR = 86% 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%

33 Caelyx: 3-4 drug combinations PADPalumbo VDDJakubowiak VDTChanan-Kan na 81 (1-yr) 97 (1-yr) 2544RDDBaz nana4830ThaDDOffidani RVDDJakubowiak nana1822 No of pts Median age ORR (%) VGPR (%) 2 yrs PFS (%) 2-yrs OS (%) Max haemat toxicity Non-haemat toxicity

34 Caelyx + new-drugs nel MM recidivato/refrattario

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

36 Response Rate Bortezomib (n = 322) CAELYX + Bortezomib (n = 324) P-value Total (CR + nCR + PR) 41%44%.43 CRnCR2%8%4%9% PR39%40% CR + VGPR 19%27%.0157 Duration of response 7.0 months ( ) 10.2 months ( ).0008 Orlowski et al. J Clin Oncol. 2007;25:

37 Time-to-Progression Orlowski et al. J Clin Oncol. 2007;25:

38

39 Selected Adverse Events of Interest Bortezomib (n = 318) CAELYX + Bortezomib (n = 318) Total Grade 3/4 Total Peripheral neuropathy 39%9%35%4% Febrile neutropenia 2%2%3%3% Bleeding/hemorrhage9%1%14%4% Thromboembolic events 1%1%1%1% Cardiac events 7%3%10%2% Alopecia1%02%0 Orlowski et al. J Clin Oncol. 2007;25:

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

41 Dex: 20 mg/d Thal: 100 mg/d (ameneded to 50 mg) Bort: 1.3 mg/m 2 (amended to 1, 4, 11) Doxil: 30 mg/m Thalidomide Day DDDDBBBB DINDUCTION CONSOLIDATION DDDDBBBB 20 mg/d (amended to 1,2 and 8,9) 1 mg/m 2 (amended to 1 and 8) Day D Thalidomide 100 mg/d 20 mg/d 6 ALTERNATING CYCLES EVERY 28 DAYS MAINTENANCE Thalidomide 100 mg/d (amended to 50 mg/d)ThaDD-V

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

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

44 ThaDD-V (44 pts) Outcomes PR PR VGPR VGPR nCR nCR Follow-up mediano (mesi) 2-yrs TTP (%) 2-yrs PFS (%) 2-yrs OS (%) My-VTD (42 pts) 73na ThaDD-V vs My-VTD: outcomes

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

46 ThaDD-V vs My-VTD: eventi avversi grado 3-4 Eventi avversi NeutropeniaPiastrinopeniaInfezioniAlopeciaEmorragiaTVPNeuropatiaPPE Eventi cardiaci Totale eventi ThaDD-V (44 pts) 4 (9) 7 (16) 7 (15) 00 2 (4.5) 5 (11) 0025 My-VTD (42 pts) 10 (24) 12 (29) 5 (12)* 7 (17) 2 (5) 1 (2) 0038 * 10 (24%) grado 2 e 2 (5%) grado 3 episodi di neutropenia febbrile

47 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 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) 6/9 prior bortezomib (3 refractory) 7/9 orior anthracyclines 7/9 orior anthracyclines 9/9 prior corticosteroids 9/9 prior corticosteroids 7/9 prior stem cell transplantation 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

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


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