Post on 09-Feb-2022
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