Carfilzomib, Cyclophosphamide and

Dexamethasone (CCd ) for Newly Diagnosed

Multiple Myeloma (MM) Patients

A. Palumbo 1, S. Bringhen 1, O. Villani 2, A. Siniscalchi 3, E. Russo 4, G. Uccello 5, C. Cerrato 1, M. Gilestro 1, D. Rossi 6 and M. Boccadoro 1.

1Division of Hematology, University of Torino, Torino, I, EU; 2Department of Onco-Hematology, IRCCS, Centro di Riferime nto Oncologico della Basilicata, Rionero in

Vulture (PZ), Italy; 3Division of Hematology, Sant’Eugenio Hospital, Roma, Italy; 4Hematology, Umberto I Hospital, University, Roma, Italy; 5Hematology, Ospedale Ferrarotto, Catania, Italy;

6Division of Hematology, BRMA – Amedeo Avogadro Universt ity of Eastern Piedmont, Novara, Italy.

GIMEMA: Italian Multiple Myeloma Network

Disclosures for Palumbo Antonio, MD

Disclosures for Palumbo Antonio, MD

Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millenium, OnyxHonoraria

Scientific Advisory Board

Speakers Bureau

No relevant conflicts of interest to declareMajor Stockholder

Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millenium, OnyxConsultant

No relevant conflicts of interest to declareEmployee

No relevant conflicts of interest to declareResearch Support/P.I.

No relevant conflicts of interest to declare

No relevant conflicts of interest to declare

Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millenium, OnyxHonoraria

Scientific Advisory Board

Speakers Bureau

No relevant conflicts of interest to declareMajor Stockholder

Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millenium, OnyxConsultant

No relevant conflicts of interest to declareEmployee

No relevant conflicts of interest to declareResearch Support/P.I.

No relevant conflicts of interest to declare

No relevant conflicts of interest to declare

Presentation includes discussion of the off-label u se of a drug or drugs

Rationale 1

Palumbo at al, Lancet, 2006 ;367:825-31; San Miguel et al, N Eng J Med 2008;359:906-17; Palumboeet al, N Engl J Med 2012;366:1759-69; Palumbo et al, J Clin Oncol 2010;28:5101-9; Richardson et al. Blood 2010; Cavo et al. Lancet 2010; 379(9758): 2075-2085; Reader et at, Leukemia 2009;23:1337-41

Efficacy – Response

CR/nCR ≥ VGPR

Elderly

MPT 27% 36%

VMP 30%* 41%

MPR-R 33%

VMPT-VT 38%* 59%

Young

VRD 21% 57%

VTD 31% 62%

CyBorD 39% 61%

Efficacy – Response

CR/nCR ≥ VGPR

Elderly

MPT 27% 36%

VMP 30%* 41%

MPR-R 33%

VMPT-VT 38%* 59%

Young

VRD 21% 57%

VTD 31% 62%

CyBorD 39% 61%

* CR only, nCR not reported

Rationale 2

Safety – Grade 3-4 AEs

ANC Platelet PNP VTE Discontinuation

Elderly

MPT 16% 3% 6% 9% 35%

VMP 40% 37% 14% 1% 33%

MPR-R ~75% 46% 0% 5% 24%

VMPT-VT 38% 22% 8% 5% 22%

Young

VRD 9% 6% 2% 6%

VTD 0% 0% 10% 3% 4%

CyBorD 13% 25% 7% 7% 9%

Safety – Grade 3-4 AEs

ANC Platelet PNP VTE Discontinuation

Elderly

MPT 16% 3% 6% 9% 35%

VMP 40% 37% 14% 1% 33%

MPR-R ~75% 46% 0% 5% 24%

VMPT-VT 38% 22% 8% 5% 22%

Young

VRD 9% 6% 2% 6%

VTD 0% 0% 10% 3% 4%

CyBorD 13% 25% 7% 7% 9%

ANC, Absolute neutrophils count; PNP, peripheral neuropathy; VTE, venous thromboembolism

Palumbo at al, Lancet, 2006 ;367:825-31.Fayers et al, Blood 2011; 118:1239-47; San Miguel et al, N Eng J Med 2008;359:906-17; Palumboe et al, N Engl J Med 2012;366:1759-69; Palumbo et al, J Clin Oncol 2010;28:5101-9; Richardson et al. Blood 2010; Cavo et al. Lancet 2010; 379(9758): 2075-2085; Reader et at, Leukemia 2009;23:1337-41

Primary objectives and Key Eligibility Criteria

Primary objectives• Safety: grade 4 neutropenia > 3 days

grade 4 thrombocytopenia >7 days grade ≥ 3 non-haematologic toxicity.

• Efficacy: partial response (PR)

Inclusion criteria• Symptomatic newly diagnosed MM• ≥ 65 years or ineligible for autologous stem cell transplantation• Measurable disease • Karnofsky performance status ≥60%

Exclusion criteria• Platelets < 50 x 109/L , ANC < 1 x 109/L • Creatinine clearance < 15 mL/minute • Peripheral neuropathy > CTCAE grade 2• Serious co-morbidities

Assessment of response was performed according to the International Myeloma Working Group criteria (Durie BGM et al, Leukemia2006: 20: 1467–1473) with the addition of nCR. Assessment of adverse events was performed according to the National Cancer Institute Common Terminology Criteria of Adverse Events (CTCAE version 4.0, http://ctep.cancer.gov/forms/CTCAEv4.pdf)

• Phase II• Multicenter (10 centres)

Study design

CYCLE 1 CYCLE 2 CYCLE 3 CYCLE 5

Dexamethasone40 mg orally

Cyphosphamide300 mg/m 2 orally

CarfilzomibDose (mg/m 2)

Dosing

Cycle day 1 2 15 16 1 2 8 9 1516 22

20 36 36 36 36 36

1 2 8 9 1516 22 1 2 8 9 1516 22

CYCLE 1 CYCLE 2 CYCLE 9 MAINTENANCE

36 36 36

1 2 15 16 1 2 15 16

36 36 36 3636 36

Response Assessments

CYCLE 1 CYCLE 2 CYCLE 3 CYCLE 5

Dexamethasone40 mg orally

Cyphosphamide300 mg/m 2 orally

CarfilzomibDose (mg/m 2)

Dosing

Cycle day 1 2 15 16 1 2 8 9 1516 22

20 36 36 36 36 36

1 2 8 9 1516 22 1 2 8 9 1516 22

CYCLE 1 CYCLE 2 CYCLE 9 MAINTENANCE

36 36 36

1 2 15 16 1 2 15 16

36 36 36 3636 36

Response Assessments

CYCLE 1 CYCLE 2 CYCLE 3 CYCLE 5

Dexamethasone40 mg orally

Cyphosphamide300 mg/m 2 orally

CarfilzomibDose (mg/m 2)

Dosing

Cycle day 1 2 15 16 1 2 8 9 1516 22

20 36 36 36 36 36

1 2 8 9 1516 22 1 2 8 9 1516 22

CYCLE 1 CYCLE 2 CYCLE 9 MAINTENANCECYCLE 1 CYCLE 2 CYCLE 9 MAINTENANCE

36 36 36

1 2 15 16 1 2 15 16

36 36 36 3636 36

Response Assessments

CCd Induction C MaintenanceCycles 1-9 Until progression

CCd Induction C MaintenanceCycles 1-9 Until progression

Patient Characteristics

No. of patients 58

Median age (range) 71 (55-86)≥ 75 years 16 (28%)

ISS stageI 16 (27%)II 19 (33%)III 23 (40%)

Chromosome abnormalitiest(4;14) 9/51 (18%)Del17p 8/51 (16%)t(14;16) 1/51 (2%)Unfavorable profile* 18/51 (35%)

No. of patients 58

Median age (range) 71 (55-86)≥ 75 years 16 (28%)

ISS stageI 16 (27%)II 19 (33%)III 23 (40%)

Chromosome abnormalitiest(4;14) 9/51 (18%)Del17p 8/51 (16%)t(14;16) 1/51 (2%)Unfavorable profile* 18/51 (35%)

* Defined as t(4;14) or Del17 or t(14;16)

Response rate by treatment duration%

of p

atie

nts

Response rate by treatment duration%

of p

atie

nts

Time to response

Median treatment duration, cycles (range): 5 (1-9)

% o

f pat

ient

s

Months

PR

sCR/CR/nCR

VGPR

0.00

0.25

0.50

0.75

1.00

0.0

0.00

0.25

0.50

0.75

1.00

0.0 2.5 5.0 7.5 10.0 12.5

0.00

0.25

0.50

0.75

1.00

% o

f pat

ient

s

Months

PR

sCR/CR/nCR

VGPR

0.00

0.25

0.50

0.75

1.00

0.0

0.00

0.25

0.50

0.75

1.00

0.0 2.5 5.0 7.5 10.0 12.5

0.00

0.25

0.50

0.75

1.00

0.00

0.25

0.50

0.75

1.00

0.0

0.00

0.25

0.50

0.75

1.00

0.0 2.5 5.0 7.5 10.0 12.5

0.00

0.25

0.50

0.75

1.00

Best Response*Subgroup analysis

*Assessed by modified IMWG Uniform Criteria with the addition of nCR** Defined as presence of t(4;14) or t(14;16) or del17p

% o

f pat

ient

s

ISS stage FISH risk

Percent of patients

Hematologic Adverse Events – All grades

Percent of patients

Non-hematologic Adverse EventsAll grades

No difference between patients younger and older th an 75 yearsG3 cardiac AEs: IMA, FA; G4 gastrointestinal AEs: ileum perforation; G3 infections: pneumonia, bronchitis

Progression -Free and Overall Survival

Time (months)

Pat

ient

s (%

)

0.00

0.25

0.50

0.75

1.00

0.0 2.5 5.0 7.5 10.0 12.5 15.0

Time (months)

Pat

ient

s (%

)

0.00

0.25

0.50

0.75

1.00

0.0 2.5 5.0 7.5 10.0 12.5 15.0

0.00

0.25

0.50

0.75

1.00

0.0 2.5 5.0 7.5 10.0 12.5 15.0

0.00

0.25

0.50

0.75

1.00

0.0 2.5 5.0 7.5 10.0 12.5 15.0

1-year PFS

88%

1-year PFS

88%

0.00

0.25

0.50

0.75

1.00

0.0 2.5 5.0 7.5 10.0 12.5 15.0

Time (months)

0.00

0.25

0.50

0.75

1.00

0.0 2.5 5.0 7.5 10.0 12.5 15.0

Time (months)

1-year OS

87%

1-year OS

87%

PFS OS

ConclusionsCCd MPT VMP

Response rates

≥ VGPR 77% 36% 41%

nCR/CR/sCR 53% 27% 30%*

sCR 23% - -

Grade 3-4 AEs

ANC 15% 16% 40%

Platelets 5% 3% 37%

PNP 0% 6% 14%

VTE 0% 9% 1%

Discontinuation 12% 35% 33%

CCd MPT VMP

Response rates

≥ VGPR 77% 36% 41%

nCR/CR/sCR 53% 27% 30%*

sCR 23% - -

Grade 3-4 AEs

ANC 15% 16% 40%

Platelets 5% 3% 37%

PNP 0% 6% 14%

VTE 0% 9% 1%

Discontinuation 12% 35% 33%

* CR only, nCR not reportedPalumbo at al, Lancet, 2006 ;367:825-31.Fayers et al, Blood 2011; 118:1239-47; San Miguel et al, N Eng J Med 2008;359:906-17

We Are Grateful to All Patients, Nurses and Physicians of the Participating Centers

1. ALESSANDRIA Levis, Baraldi2. ANCONA Leoni, Offidani3. AOSTA Di Vito4. ASCOLI PICENO Galieni5. ASTI Favro, Ciravegna6. AVELLINO Cantore, Volpe7. AVIANO Tirelli, Rupolo8. BARI Vacca, Ria9. BARI Liso10. BELLUNO Pianezze11. BENEVENTO Di Lonardo, Vallone12. BERGAMO Rambaldi, Galli13. BOLOGNA Baccarani,Cavo14. BOLZANO Cortellazzo, Pescosta15. BRA Vanni, Stefani16. BRESCIA Rossi, Crippa17. BRESCIA Russo, Malagola18. BRINDISI Quarta19. CAGLIARI Angelucci, Derudas20. CAGLIARI La Nasa, Ledda21. CAMPOBASSO Storti22. CANDIOLO Aglietta, Capaldi23. CATANIA Di Raimondo24. CATANZARO Peta, Piro25. CATTOLICA Pasquini26. CESENA Guardigni27. CIRIE' Girotto, Freilone28. COSENZA Morabito29. CREMONA Lanza30. CUNEO Gallamini, Grasso31. FIRENZE Bosi/Nozzoli32. FOGGIA Capalbo33. FORLI’ Amadori, Gentilini34. FROSINONE Sala35. GALLARATE Mozzana, Ciambelli36. GENOVA Gobbi, Canepa37. FORLI’ Amadori, Gentilini38. GENOVA Gobbi, Canepa

39. GENOVA Carella, Spriano40. GENOVA Bacigalupo, Dominietto41. IVREA Girotto, Aitoro42. LATINA De Blasio43. LATINA Cimino44. LECCE Di Renzo45. MATERA Fragasso46. MESSINA Brugiatelli47. MESSINA Musolino48. MILANO Corradini, Montefusco49. MILANO Morra50. MILANO Ciceri51. MILANO Lambertenghi, Baldini52. MILANO Gianni53. MODENA Marasca54. MODENA Sacchi55. MONZA Pogliani, Rossini56. NAPOLI Pane,Catalano57. NAPOLI Ferrara58. NAPOLI Mettivier59. NOCERA INF. D’Arco, Califano60. NOVARA Gaidano, Rossi61. NUORO Gabbas62. ORBASSANO Saglio, Guglielmelli63. PADOVA Semenzato, Zambello64. PALERMO Mirto, Cangialosi65. PARMA Rizzoli, Giuliani66. PAVIA Lazzarino, Corso67. PERUGIA Martelli, Ballanti68. PESARO Visani, Leopardi69. PESCARA Fioritoni, Spadano70. PIACENZA Cavanna, Lazzaro71. PINEROLO Griso72. PISA Petrini/Benedetti73. POTENZA Ricciuti, Vertone74. RAVENNA Zaccaria, Cellini75. REGGIO CALABRIA Nobile, Callea76. REGGIO EMILIA Gugliotta, Masini

77. RIMINI Pasquini, Fattori78. RIONERO VULTURE Musto79. RIETI Capparella80. ROMA Foà, Petrucci81. ROMA De Fabritiis, Caravita82. ROMA Andriani83. ROMA Annino, Bongarzoni84. ROMA Leone, De Stefano85. ROMA Petti, Pisani86. ROMA Majolino, De Rosa87. ROMA Amadori88. ROMA Avvisati89. ROMA Recine90. ROZZANO Santoro, Nozza91. S. G. ROTONDO Cascavilla, Falcone92. SASSARI Dore, Podda93. SIENA Lauria, Gozzetti94. TARANTO Mazza, Casulli95. TERNI Liberati96. TORINO Boccadoro97. TORINO Pregno, Benevolo98. TORINO Tarella, Gottardi99. TREVISO Gherlinzoni100. TRICASE Pavone101. TRIESTE De Sabbata102. UDINE Fanin, Patriarca103. VENEZIA Chisesi104. VERBANIA Montanara, Luraschi105. VERCELLI Santagostino106. VERONA Pizzolo, Meneghini107. VICENZA Rodeghiero, Elice108. VITERBO Montanaro109. ISRAEL Nagler110. JERUSALEM Ben Yehuda111. KEFAR SABAH Manor112. ZERIFIM Kornberg113. HAIFA Attias