Gammie T, Lu CY, Ud-Din, PLoS One, 2015

Mario Boccadoro

DIVISIONE UNIVERSITARIA DI EMATOLOGIA

Roma 1-12-2015

Mieloma Multiplo: Malattia Rara

Malattia rara, rarissima?

Incidenza nelle varie aziende

Immissione in CommercioMolte orphan drugs poche AICCombinazioniManaged entry agreement

Mieloma multiplo: malattia rara

• eccezionali progressi• rete

Malattia rara, rarissima?

Incidenza nelle varie aziende

Immissione in CommercioMolte orphan drugs poche AICCombinazioniManaged entry agreement

Mieloma multiplo: malattia rara

• eccezionali progressi• rete

Surv

ival %

100

50

Median survival = 24 - 30 months

Multiple Myeloma - incurable disease

Complete Response: 1-3%

Kumar S, Leukemia. 2014 May;28(5):1122-8.

Median survival 6 years

Continuous improvement in overall survival

8Bergsagel MD 2104 ASCO Educational Book

Malattia rara, rarissima?

Incidenza nelle varie aziende

Immissione in CommercioMolte orphan drugs poche AICCombinazioniManaged entry agreement

Mieloma multiplo: malattia rara

• eccezionali progressi• rete

BOARD

Baldini Luca

Corso Alessandro

Di Raimondo Francesco

Morabito Fortunato

Musto Pellegrino

Offidani Massimo

Patriarca Francesca

Petrucci Maria Teresa

Tosi Patrizia

Mieloma Multiplo Working Party

Chairman

Mario Boccadoro

Co-chairman

Michele Cavo

Antonio Palumbo

We Are Grateful to All Patients, Nurses and

Physicians of the Participating Centers

1. ALESSANDRIA Levis, Baraldi

2. ANCONA Leoni, Offidani

3. AOSTA Di Vito

4. ASCOLI PICENO Galieni

5. ASTI Favro, Ciravegna

6. AVELLINO Cantore, Volpe

7. AVIANO Tirelli, Rupolo

8. BARI Vacca, Ria

9. BARI Liso

10. BELLUNO Pianezze

11. BENEVENTO Di Lonardo, Vallone

12. BERGAMO Rambaldi, Galli

13. BOLOGNA Baccarani,Cavo

14. BOLZANO Cortellazzo, Pescosta

15. BRA Vanni, Stefani

16. BRESCIA Rossi, Crippa

17. BRESCIA Russo, Malagola

18. BRINDISI Quarta

19. CAGLIARI Angelucci, Derudas

20. CAGLIARI La Nasa, Ledda

21. CAMPOBASSO Storti

22. CANDIOLO Aglietta, Capaldi

23. CATANIA Di Raimondo

24. CATANZARO Peta, Piro

25. CATTOLICA Pasquini

26. CESENA Guardigni

27. CIRIE' Girotto, Freilone

28. COSENZA Morabito

29. CREMONA Lanza

30. CUNEO Gallamini, Grasso

31. FIRENZE Bosi/Nozzoli

32. FOGGIA Capalbo

33. FORLI’ Amadori, Gentilini

34. FROSINONE Sala

35. GALLARATE Mozzana, Ciambelli

36. GENOVA Gobbi, Canepa

37. FORLI’ Amadori, Gentilini

38. GENOVA Gobbi, Canepa

39. GENOVA Carella, Spriano

40. GENOVA Bacigalupo, Dominietto

41. IVREA Girotto, Aitoro

42. LATINA De Blasio

43. LATINA Cimino

44. LECCE Di Renzo

45. MATERA Fragasso

46. MESSINA Brugiatelli

47. MESSINA Musolino

48. MILANO Corradini, Montefusco

49. MILANO Morra

50. MILANO Ciceri

51. MILANO Lambertenghi, Baldini

52. MILANO Gianni

53. MODENA Marasca

54. MODENA Sacchi

55. MONZA Pogliani, Rossini

56. NAPOLI Pane,Catalano

57. NAPOLI Ferrara

58. NAPOLI Mettivier

59. NOCERA INF. D’Arco, Califano

60. NOVARA Gaidano, Rossi

61. NUORO Gabbas

62. ORBASSANO Saglio, Guglielmelli

63. PADOVA Semenzato, Zambello

64. PALERMO Mirto, Cangialosi

65. PARMA Rizzoli, Giuliani

66. PAVIA Lazzarino, Corso

67. PERUGIA Martelli, Ballanti

68. PESARO Visani, Leopardi

69. PESCARA Fioritoni, Spadano

70. PIACENZA Cavanna, Lazzaro

71. PINEROLO Griso

72. PISA Petrini/Benedetti

73. POTENZA Ricciuti, Vertone

74. RAVENNA Zaccaria, Cellini

75. REGGIO CALABRIA Nobile, Callea

76. REGGIO EMILIA Gugliotta, Masini

77. RIMINI Pasquini, Fattori

78. RIONERO VULTURE Musto

79. RIETI Capparella

80. ROMA Foà, Petrucci

81. ROMA De Fabritiis, Caravita

82. ROMA Andriani

83. ROMA Annino, Bongarzoni

84. ROMA Leone, De Stefano

85. ROMA Petti, Pisani

86. ROMA Majolino, De Rosa

87. ROMA Amadori

88. ROMA Avvisati

89. ROMA Recine

90. ROZZANO Santoro, Nozza

91. S. G. ROTONDO Cascavilla, Falcone

92. SASSARI Dore, Podda

93. SIENA Lauria, Gozzetti

94. TARANTO Mazza, Casulli

95. TERNI Liberati

96. TORINO Boccadoro

97. TORINO Pregno, Benevolo

98. TORINO Tarella, Gottardi

99. TREVISO Gherlinzoni

100. TRICASE Pavone

101. TRIESTE De Sabbata

102. UDINE Fanin, Patriarca

103. VENEZIA Chisesi

104. VERBANIA Montanara, Luraschi

105. VERCELLI Santagostino

106. VERONA Pizzolo, Meneghini

107. VICENZA Rodeghiero, Elice

108. VITERBO Montanaro

109. ISRAEL Nagler

110. JERUSALEM Ben Yehuda

111. KEFAR SABAH Manor

112. ZERIFIM Kornberg

113. HAIFA Attias

Malattia rara, rarissima?

Incidenza nelle varie aziende

Immissione in CommercioMolte orphan drugs poche AICCombinazioniManaged entry agreement

Mieloma multiplo: malattia rara

• eccezionali progressi• rete

fewer than 1 in 2,000 people. Diseases that are statistically rare, but

life-threatening, chronically debilitating, or inadequately treated

Orpha Number Disease Incidence

Prevalence

29073 Multiple Myeloma 11,9P 6.0 I

Mieloma Multiplo: malattie diverse

Non alterazioni molecolari

Presenza di t(4;14) o del(17p)

Kumar S, Leukemia. 2014 May;28(5):1122-8

t(4;14) or del(17p) about 15% of myeloma patients

Mieloma Multiplo

Ricoveri sul totale regionale presso

Città della Salute 30%

Provenienza pazienti ricoverati presso Città della Salute

Altre Nazioni ??

Calcolo prevalenza malattie rare nei vari centri??

14%

Malattia rara, rarissima?

Incidenza nelle varie aziende

Immissione in Commercio

Molte orphan drugs poche AIC

Combinazioni

Managed entry agreement

Mieloma multiplo: malattia rara

• eccezionali progressi

• rete

(3E,5E)-3,5-bis[(4-fluoro-3-nitrophenyl)methylidene]-1-(prop-2-enoyl)azepan-4-0ne

17-allylamino-17-demethoxygeldanamycin

6-[4-Deoxy-4-[(2E,4E)-tetradecadienoylglycyl]amino-L-glycero-B-L-manno-heptopyranosyl]amino-9H-purine

Acadesine

Aplidine

Bortezomib

Carfilzomib

Daratumumab

Dexamethasone (40 mg tablet)

Doxorubicin hydrochloride (liposomal)

Elotuzumab

Filanesib

Genetically modified serotype 5/3 adenovirus coding for granulocyte-macrophage colony-stimulating factor

Human anti-intercellular adhesion molecule-1 monoclonal antibody

Humanized immunoglobulin monoclonal antibody against CD38

Imexon

Ixazomib citrate

Lenalidomide

Marizomib

Maytansinoid-conjugated humanized monoclonal antibody against CD56

Melphalan

Milatuzumab

N-(methyl-diazacyclohexyl-methylbenzamide)-azaphenyl-aminothiopyrrole

N2'-Deacetyl-N2'-[4-methyl-4-(oxobuthyldithio)-1-oxopentyl]-maytansine-chimerized anti- CD138 IgG4 monoclonal antibody

Oprozomib

Panobinostat

Perifosine

Plitidepsin

Pomalidomide

combinant histidine-tagged idiotype immunoglobulin Fab fragment of clonal B-cell receptors

Recombinant human monoclonal IgM antibody targeting glucose-regulated protein 78

Siltuximab

Synthetic signal peptide of human Mucin-1 (amino acids 1-21)

Thalidomide

Vorinostat

Drug with Orphan designation 2015

ALKERAN

FARYDAK

IMNOVID

KYPROLIS

MOZOBIL

POMALYST

REVLIMID

THALIDOMIDE CELGENE

THALOMID

VELCADE

Marketing Authorization with orphan designation

FARYDAK

IMNOVID

MOZOBIL

REVLIMID

THALIDOMIDE CELGENE

USA EU

Malattia rara, rarissima?

Incidenza nelle varie aziende

Immissione in Commercio

Molte orphan drugs poche AIC

Combinazioni

Managed entry agreement

Mieloma multiplo: malattia rara

• eccezionali progressi

• rete

21

Phase 2 Trial of Carfilzomib-Lenalidomide-

Dexamethasone (CRd) in TE NDMM patients

• Phase 2, open-label, single-centre study

N = 31

patients

with

NDMM

CRd:

CFZ: 36 mg/m2,a,

30 min, D1–2, 8–9,

15–16

LEN: 25 mg, D1–21

DEX: 40 mg, weekly

Four 28-day cycles

CRd:

CFZ: LTD, D1–2,

15–16

LEN: LTD, D1–21

DEX: LTD, weekly

Ten 28-day cycles

Induction Maintenance*Consolidation

CRd:

CFZ: LTD, D1–2,

8–9,15–16

LEN:15-25, D1–21

DEX: 20 mg or LTD

weekly

Four 28-day cycles

ASCT

• Primary endpoint: sCR after consolidation;

secondary endpoints: ORR, survival, DoR, TTP, safety and tolerability

• Median age was 62 years, 50% of patients had high-risk cytogenetics

Zimmerman TM, et al. EHA 2014: abstract P347. Poster presentation.

NCT01816971.

a 20 mg/m2 for Cycle 1, D1-2

CRd, carfilzomib, Lenalidomide, low-dose dexamethasone; LTD, last tolerated dose;

TE, transplant-eligible

* Off-protocol: LEN monotherapy maintenance at LTD from cycle 19

22

Phase 2 Trial of CRd in NDMM

Summary of Outcomes

Efficacy

• ORR (≥ PR) after 4 cycles of

CRd was 96%

• sCR + CR = 79%

Zimmerman TM, et al. EHA 2014: abstract P347. Poster presentation.

64% 92% 100%

Mieloma multiplo: malattia rara

Nuove medicine con differente meccanismo d’azione

Combinazioniinibitori del proteasomaimmunomudulating drugsanticorpi monoclonali

Aumento efficacia -> Guarigione?

Aumento costi

Malattia rara, rarissima?

Incidenza nelle varie aziende

Immissione in Commercio

Molte orphan drugs poche AIC

Combinazioni

Managed entry agreement

Mieloma multiplo: malattia rara

• eccezionali progressi

• rete

Conclusioni

Sempre più malattie rare

Sempre piu farmaci mirati

Precision/personalized medicine

Doctors have always recognized that everypatient is uniquePresident Obama, January 2015