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Dalla terapia ad alte dosi Dalla terapia ad alte dosi alla talidomide alla talidomide
e agli inibitori del proteasoma: e agli inibitori del proteasoma: una storia terapeutica in evoluzioneuna storia terapeutica in evoluzione
Roma, 3 febbraio 2006Roma, 3 febbraio 2006
Targeted therapies nella pratica clinica delle neoplasieTargeted therapies nella pratica clinica delle neoplasie
ematologiche - Mieloma multiploematologiche - Mieloma multiplo
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
Maria Teresa AmbrosiniMaria Teresa Ambrosini
MM* (all 3 criteria required) Monoclonal plasma cells in the bone marrow 10% and/or
presence of a biopsy-proven plasmacytoma
Monoclonal protein present in the serum and/or urine†
Myeloma-related organ dysfunction (1 or more)Myeloma-related organ dysfunction (1 or more)††††
(C)(C) Calcium elevation in the blood (serum calcium >10.5 Calcium elevation in the blood (serum calcium >10.5 mg/L mg/L
or upper limit of normal)or upper limit of normal) (R) (R) Renal insufficiency (serum creatinine >2 mg/dL)Renal insufficiency (serum creatinine >2 mg/dL) (A) (A) Anemia (hemoglobin <10 g/dL or 2g <normal)Anemia (hemoglobin <10 g/dL or 2g <normal) (B)(B) Lytic bone lesions or osteoporosisLytic bone lesions or osteoporosis****
Criteria for Diagnosis of MMCriteria for Diagnosis of MM
*Note: These criteria identify Stage IB and Stages II and III A/B myeloma by Durie/Salmon stage. Stage IA becomes smoldering or indolent myeloma; †If no monoclonal protein is detected (nonsecretory disease), then 30% monoclonal bone marrow plasma cells and/or a biopsy-proven plasmacytoma required; ††A variety of other types of end organ dysfunctions can occasionally occur and lead to a need for therapy. Such dysfunction is sufficient to support classification as myeloma if proven to be myeloma related; **If a solitary (biopsy-proven) plasmacytoma or osteoporosis alone (without fractures) are the sole defining criteria, then 30% plasma cells are required in the bone marrow
Durie BGM et al. Hematol J. 2003;4:379DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
Melphalan and Prednisone (MP)Melphalan and Prednisone (MP)
• Conventional chemotherapy in use for over 40 Conventional chemotherapy in use for over 40 yearsyears
• Partial Response: 50-60%Partial Response: 50-60%
• Complete ReComplete Response 1% sponse 1%
• Median Overall Survival 3 yearsMedian Overall Survival 3 years
• Equivalent mortality and survival between MP Equivalent mortality and survival between MP and combination chemotherapyand combination chemotherapy
Myeloma Trialists' Collaborative Group. J Clin Oncol. 1998;16:3832
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
DOSEDOSE
RE
SP
ON
SE
RE
SP
ON
SE
Melphalan dose-response curveMelphalan dose-response curve
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
High dose Melphalan with Autologous Stem Cell High dose Melphalan with Autologous Stem Cell TransplantationTransplantation
• Complete ReComplete Response rsponse rate increased from ate increased from 1 - 3% to 30 - 50%1 - 3% to 30 - 50%
• Remission extended from 18 to 30 Remission extended from 18 to 30 monthsmonths
• Overall survival doubled from 30 to 60 Overall survival doubled from 30 to 60 monthsmonths
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
Randomized studies: High Dose Therapy Randomized studies: High Dose Therapy versusversus Standard ChemotherapyStandard Chemotherapy
1. Attal M et al. N Engl J Med. 1996;335:912. Child JA et al. N Engl J Med. 2003;348:1875
60453015
P=0.03Conventional
Transplant
Ove
rall
Su
rviv
al (
%)
100
75
50
25
Treatment (mo)
IFM901
Transplant
80
25
50
75
100
0
0 20 40 60
Conventional
Treatment (mo)
Ove
rall
Su
rviv
al (
%)
P = 0.04
0
MRC72
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
For Newly Diagnosed MMFor Newly Diagnosed MM
Attal M et al. N Engl J Med. 2003;349:2495Cavo M et al. Hematol J 2003;4 abstract P 10.2.5Fermand JP et al. Blood. 2001;98 abstract #3387Sonneveld P et al. Blood. 2004;104 abstract #948
Single vs Double ASCTSingle vs Double ASCT
2424110110DoubleDoubleNo No differencedifference
2525
3434
2121110110SingleSingleCavo et alCavo et al
2222
2020
No No differencedifference
3030
2525
Median EFS (mo)
37379999DoubleDouble
55551313148148SingleSingleSonneveld et al Sonneveld et al (HOVON 24)(HOVON 24)
No No differencedifference
42429494SingleSingleFermand et alFermand et al
50502828155155DoubleDouble
58585050200200DoubleDouble
48484242199199SingleSingleAttal et alAttal et al
Median OS (mo)
CR (%)nASCTStudy
P=NS
P=NS P<0.05
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
P=NS
P=0.002 P=0.02 P=NS
P=0.03 P=0.01
Multiple MyelomaMultiple MyelomaS
urv
ival
%S
urv
ival
%
100100
5050
Median survival = 3-5-yearsMedian survival = 3-5-yearsDIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
Multiple MyelomaMultiple Myeloma
SEEDSEED
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
SOILSOIL
Bruno B et al. Lancet Oncology 2003;4:379DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
Bruno B et al. Lancet Oncology 2003;4:379DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
ThalidomideThalidomide• Precise mechanism of action not yet understood Precise mechanism of action not yet understood
Multiple actions:Multiple actions:
• antiangiogenic effects that provide the rationale antiangiogenic effects that provide the rationale for its use in MMfor its use in MM
• immunomodulatory effectimmunomodulatory effect
• apoptotic effectapoptotic effect
• Thalidomide was first shown to be effective as a single Thalidomide was first shown to be effective as a single agent in patiens with relapsed and refractory disease agent in patiens with relapsed and refractory disease
(Singhal S (Singhal S et al. N Engl J Med. 1999;341:1565)
• Numerous subsequent studies have confirmed its Numerous subsequent studies have confirmed its efficacy with a response rate of 30% alone, 50% when efficacy with a response rate of 30% alone, 50% when used in combination with dexamethasone and 70% with used in combination with dexamethasone and 70% with chemotherapy.chemotherapy.
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
Thalidomide/dexamethasone combination Thalidomide/dexamethasone combination
Cavo
Blood 2005
Ludwig
ASH 2005
Rajkumar
JCO 2006
Study
DVT (15), constipation (9), infections (4),neuropathy (4), deaths (6)
76%13%100 (*)
ToxicityCR+PRCR/nCRNo
DVT (20),neuropathy (7),skin rash (4), deaths (6)63%4% (CR)103 (*)
DVT (5), neuropathy (15), skin rash (7)52%22%60 (*)
(*) in untreated patients(°) in relapsed patients
Palumbo
Hematol J 2004
DVT (2), neuropathy( 20), confusion (8), skin rash (4)52%na120 (°)
na 55%neuropathy, confusion, constipation, sonnolence
Dimopoulos
Ann Oncol 200144 (°)
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
Thalidomide/Dexamethasone vs Dexamethasone Thalidomide/Dexamethasone vs Dexamethasone in Newly Diagnosed Multiple Myelomain Newly Diagnosed Multiple Myeloma
Phase III Clinical Trial, newly diagnosed MM for whom Phase III Clinical Trial, newly diagnosed MM for whom stem cell transplantation was considerate appropriatestem cell transplantation was considerate appropriate
Thalidomide 200 mg daily p.o. + Dexamethasone 40 mg Thalidomide 200 mg daily p.o. + Dexamethasone 40 mg p.o. on days 1-4, 9-12, 17-20 or Dexamethasone alonep.o. on days 1-4, 9-12, 17-20 or Dexamethasone alone
Every 4 weekEvery 4 week
Rajkumar SV et al. J Clin Oncol 2006;24:1Rajkumar SV et al. J Clin Oncol 2006;24:1
EndpointDex
(n=100)Thal/Dex
(n=99)
42• Disease progression within first 4 mo, %
1.1 1.1 • Median time to response, mo
41 (41)62 (63)• Response rate, n (%)*
*Best response within 4 courses
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
Thalidomide/Dexamethasone vs Dexamethasone: Thalidomide/Dexamethasone vs Dexamethasone: Drug-Related Adverse EventsDrug-Related Adverse Events
Dex, n (%) (n=102)
Thal/Dex, n (%) (n=102)Drug-Related Adverse Event
21 (21)46 (45)Total
18 (18)35 (34)Any toxicity ≥ grade 4
4 (4)7 (7)Neuropathy ≥ grade 3
0 (0)1 (1)Sinus bradycardia ≥ grade 3
0 (0)4 (4)Rash ≥ grade 3
3 (3)17 (17)DVT ≥ grade 3
Deaths within 4 cycles: Thal/Dex, 7%; Dex, 11%
Rajkumar SV et al. J Clin Oncol 2006;24:1Rajkumar SV et al. J Clin Oncol 2006;24:1
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
Thalidomide Chemotherapy combinations
(*) in untreated patients(°) in relapsed patients
DVT (4), neutropenia (6), DVT (4), neutropenia (6), thrombocytopenia (6), thrombocytopenia (6),
constipation (4), constipation (4), neuropathy (2) neuropathy (2)
64%10%T-VAD (*)
Vcr + Adria + Dex + THAL39
Zervas
Ann Oncol 2004
Death (4), DVT (17), infection (11),
neuropathy(31)76%28%
MPT MPT (*)
M + P + THALM + P + THAL129
Palumbo
ASH 2005
53%
CR+PR
32%32%
na
CR/nCR ToxicityRegimenNoStudy
Infections (6), Neuropathy (2), constipation (7)
CTD (°)Cy + Dex + THAL
22Garcia-SanzHemat J 2002
Schutt
Eur J Haematol 200531 T-VED (*)
Vcr + Epir + Dex +THAL19% 80%
DVT (8), neutropenia (10), DVT (8), neutropenia (10), infection (7), neuropathy infection (7), neuropathy
(20) (20)
OffidaniHaematologica 2006 50
DVd-T (°)Vcr+AdriaLipo + Dex + THAL 76%76%
DVT (6),neutropenia (8), DVT (6),neutropenia (8), constipation (1), constipation (1), neuropathy (1) neuropathy (1)
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
Thalidomide With Melphalan and Prednisone in Thalidomide With Melphalan and Prednisone in Elderly Patients With MMElderly Patients With MM
MPT Arm (Median age 72)
Melphalan, 4 mg/m2 (7 days/mo)
Prednisone, 40 mg/m2 (7 days/mo)
Thalidomide, 100 mg/d (continuously)*
(n=129)
MP Arm (Median age 72)
Melphalan, 4 mg/m2 (7 days/mo)
Prednisone, 40 mg/m2 (7 days/mo)
(n=126)
6 courses6 courses
NewlyNewlydiagnosed MM patients, diagnosed MM patients,
aged >65 yr aged >65 yr (n=255 as of 3/05)(n=255 as of 3/05)
*Thalidomide dose reduced to 50% if grade 2 toxicity. Follow-up ≥6 mos.
Palumbo A et al. Blood. 2005;106: abstract #779
Phase III Randomized Controlled TrialPhase III Randomized Controlled Trial
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
MPT in Elderly Patients With MM: ResponseMPT in Elderly Patients With MM: Response
NS6480OS at 36 mo
<0.00113.629.2Median EFS, mo
<0.001728CR + nCR
4560PR
47
5
2
MP, % (n=126)
<0.001
P value
16CR
76ORR
12nCR
MPT, % (n=129)
Response
Palumbo A et al. Blood. 2005;106: abstract#779
PR (>50%), nCR (IF+), CR (IF-)
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
Thromboembolism in MPT-Treated Elderly Thromboembolism in MPT-Treated Elderly Patients Reduced With ProphylaxisPatients Reduced With Prophylaxis
0.01.5Arterial occlusion
0.04.6Pulmonary thromboembolism
3.018.4DVT
With Prophylaxis(n=64)
No Prophylaxis(n=65)Adverse Event
Incidence, %
• More DVT with MPT than with MP (More DVT with MPT than with MP (PP=0.003)=0.003)
• DVT prophylaxis: enoxaparin, 0.4 mL/day for 4 monthsDVT prophylaxis: enoxaparin, 0.4 mL/day for 4 months
Palumbo A et al. Blood. 2005;106:abstract #779DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
MP vs MP-Thal and MP vs Mel100 in Newly Diagnosed MM Patients Aged 65–75 Years
Response MP(n=191)
MP-Thal (n=124)
MEL100 (n=121)
PFS 17,1 27,6 19
OS 30,3 > 55 38,6
3nd planned interim analysis 5/2005; median follow-up time = 32.2 months
Facon T et al. Blood. 2005;106 abstract#780
IFM 99-06 Trial Response to Treatment*IFM 99-06 Trial Response to Treatment*
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
RandomRandom
MPMP
MP + THALMP + THAL
2 VAD 2 VAD CTX 3g/mq CTX 3g/mq MEL100 MEL100 MEL 100 MEL 100
12 courses12 courses
12 courses12 courses
Maintenance With Thalidomide after ASCT
No maintenance Pamidronate,
90 mg/mo
Pamidronate, 90 mg/mo Thalidomide, 100 mg/day
Attal M et al. Blood. 2005;106 abstract #1148
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
Endpoint No maintenance Pam Thal/Pam P Value
Patients, n 197 195 201
4-yr EFS, % 39 37 50 0.001
4-yr OS, % 86 78 86 ns
• ASCT (MEL140 MEL200) as front line therapy
• Month 3 after 2 ASCT, if no progression
RandomRandom
CC5013 is CC5013 is more potentmore potent and and less toxicless toxic than the parent than the parent compoundcompound
Induces apoptosis in MM cellsInduces apoptosis in MM cells
Decreases binding of MM cells to bone marrow Decreases binding of MM cells to bone marrow stromal cellsstromal cells
– Inhibits cytokine production Inhibits cytokine production (IL-6, VEGF, TNF-alfa)(IL-6, VEGF, TNF-alfa)
– Blocks angiogenesisBlocks angiogenesis
Thalidomide Analog; REVLIMIDThalidomide Analog; REVLIMID™™ (CC5013) (CC5013)
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
Phase III Trial of Lenalidomide/Dex in Relapsed or Phase III Trial of Lenalidomide/Dex in Relapsed or Refractory MMRefractory MM
Lenalidomide 25 mg d 1–21Placebo d 22–28
Dex 40 mg, d 1–4, 9–12, 17–20
Placebo d 1–28Dex 40 mg, d 1–4, 9–12, 17–20
Same, exceptDex d 1–4
4 COURSES4 COURSES CONTINUECONTINUEUNTIL PDUNTIL PD
International MM-010 (51 Centers Europe/Australia/Israel): Dimopoulos (351 patients)International MM-010 (51 Centers Europe/Australia/Israel): Dimopoulos (351 patients)
Primary endpoint: TTP (by BladPrimary endpoint: TTP (by Bladé criteria)é criteria)
Secondary endpoints: OS, RR, safety, 1Secondary endpoints: OS, RR, safety, 1stst skeletal-related event, PS skeletal-related event, PS
Inclusion criteriaInclusion criteria
≤≤3 prior therapies3 prior therapies
No Dex resistanceNo Dex resistance
Normal liver/renal Normal liver/renal functionfunction
Dimopoulous M et al. Blood. 2005;106 abstract #6DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
Phase III Trial of Lenalidomide/Dex in Relapsed or Phase III Trial of Lenalidomide/Dex in Relapsed or Refractory MMRefractory MM
Endpoint Lenalidomide/Dex
Placebo/Dex P value
Time To Time To ProgressionProgression
13 mo13 mo 5 ,1 mo5 ,1 mo <0.00001<0.00001
Overall Response Overall Response RateRate
58%58% 22%22% <0.001<0.001
An independent commettee closed the study:An independent commettee closed the study:Revlimid superior to DexRevlimid superior to Dex
Dimopoulous M et al. Blood. 2005;106 abstract #6DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
BortezomibBortezomib
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALYBruno B et al. Lancet Oncology 2004
The Proteasome: A Target for
Novel Therapies
APEX : Treatment plan
273 treatment days 280 treatment days
1.3 mg/m2 IV pushDays 1, 4, 8, 11 Q3W cycle
8 cycles
1.3 mg/m2 IV pushDays 1, 8, 15, 22 Q5W cycle
4 cycles
3 cycles 5 cycles
40 mg po Days 1–4, 9–12, 17–20 Q5W cycle
40 mg po Days 1–4 Q4W cycle
Randomization
Bortezomib Dexamethasone
Induction
Maintenance
Richardson Richardson et alet al. N Engl J Med 2005;352:2487. N Engl J Med 2005;352:2487
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
APEX: OutcomeAPEX: Outcome
Time to progression (Time to progression (nn = 669) = 669)1-year survival (1-year survival (nn = 669) = 669)
Endpoint Bortezomib Dexamethasone
Time To ProgressionTime To Progression 6,2 mo6,2 mo 3,5 mo3,5 mo
Overall Survival @ 1yrOverall Survival @ 1yr 80%80% 66%66%
Richardson Richardson et alet al. N Engl J Med 2005;352:2487. N Engl J Med 2005;352:2487
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
APEX: response rates (CR, PR)APEX: response rates (CR, PR)
Median time to response (TTR)• 43 days in both armsDuration of response• Bortezomib 8.0 months• Dexamethasone 5.6 months• Median follow-up ~8.3 months
<1% nCR 25% PR
16% PR7% nCR6% CR
Bortezomib Dexamethasone
Res
po
nse
(%
)
38%
18%
P<.0001
0
10
20
30
40
50
60
70
80
90
100
<1% CR
Richardson Richardson et alet al. N Engl J Med 2005;352:2487. N Engl J Med 2005;352:2487
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
APEX: Treatment-emergent ≥ grade 3 AEs reported by ≥ 5% of patients
Patients %Patients %00 1010 2020 3030 4040 5050
Thrombocytopenia
Neutropenia
Anemia
Peripheral neuropathy
Diarrhea
Fatigue
Dyspnea
Pneumonia
Hyperglycemia
Bortezomib (n = 331) Dexamethasone ( (nn = 332) = 332)
Richardson Richardson et alet al. N Engl J Med 2005;352:2487. N Engl J Med 2005;352:2487
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
Bortezomib alone and in combination with Dexamethasone for untreated MM
Treatment• Bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11 of
21-day cycle• Dexamethasone 40 mg P.O. on days 1, 2, 4, 5, 8, 9,
11, 12 added if <PR after 2 cycles or <CR after 4 cycles
Jagannath Jagannath et alet al. Br J of Haematology 2005;129:776. Br J of Haematology 2005;129:776
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
N= 32 Bortezomib Bortezomib+Dexamethasone
CR 3% 6%
nCR 9% 19%
PR 28% 63%
PAD combination therapy (bortezomib (PS-341), PAD combination therapy (bortezomib (PS-341), Adriamycin and Dexamethasone) for untreated MMAdriamycin and Dexamethasone) for untreated MM
Oakervee Oakervee et alet al. Br J of Haematology 2005;129:755. Br J of Haematology 2005;129:755
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
Treatment
• Bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11 of 21-day cycle• Dexamethasone 40 mg on days 1-4, 8-11, 15- 18 during cycle 1, days 1-4 cycles 2-4• Doxorubicine 0 - 4,5 – 9 mg/mq on days 1-4
95%95%ORRORR
33%33%PRPR
33%33%VGPRVGPR
5%5%nCRnCR
24%24%CRCR
Response Rate:Response Rate:
VTD (VELCADEVTD (VELCADE®®, Thalidomide, Dexamethasone) as , Thalidomide, Dexamethasone) as Primary Therapy for Newly-Diagnosed MMPrimary Therapy for Newly-Diagnosed MM
Treatment:Treatment:
• Bortezomib 1.0 to 1.9 mg/mBortezomib 1.0 to 1.9 mg/m2 2 days 1, 4, 8, 11 q 28 daysdays 1, 4, 8, 11 q 28 days
• Thalidomide 100-200 mg each eveningThalidomide 100-200 mg each evening
• Dexamethasone 20 mg/mDexamethasone 20 mg/m22 days 1-4, 9-12, 17-20 q 28 days days 1-4, 9-12, 17-20 q 28 days
28- day treatment cycle, 2 cycles28- day treatment cycle, 2 cycles
Institutional experience of 36 patientsInstitutional experience of 36 patients– 92%92% Response rate (CR+PR) Response rate (CR+PR)– PBSC easily collectedPBSC easily collected
Wang Wang et alet al. . Blood Blood 2005;106 Abstract#784 2005;106 Abstract#784
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
A phase I/II study of Bortezomib plus Melphalan and A phase I/II study of Bortezomib plus Melphalan and Prednisone (V-MP) in Elderly Untreated MM patientsPrednisone (V-MP) in Elderly Untreated MM patients
Mateos Mateos et alet al. . Blood Blood 2005;106 Abstract#786 2005;106 Abstract#786
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
Treatment
V-MP 9 courses
Four 6-week courses Melphalan p.o. 9 mg/m2 on days 1-4, Prednisone p.o. 60 mg mg/m2 on days 1-4 VELCADE i.v 1,3 mg/m2 days 1, 4, 8, 11, 22, 25, 29, and 32
Five 5-week courses Melphalan p.o. 9 mg/m2 on days 1-4, Prednisone p.o. 60 mg mg/m2 on days 1-4 VELCADE i.v 1,3 mg/m2 days 1, 8, 22, and 29
V-MP: Response RatesV-MP: Response Rates (N=53) (N=53)
After 1st cycle
0%
10%
20%
30%
40%
50%
60%
70%
CR IF- CR IF+ PR
72%
6% 2%
64%
Best response (median 3 cycles)
10%
20%
30%
40%
50%
60%
70%
85%
0%CR IF- CR IF+ PR MR SD
28%
11%
45%
3%13 %
Mateos Mateos et alet al. . Blood Blood 2005;106 Abstract#786 2005;106 Abstract#786
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
V-MP: ConclusionsV-MP: Conclusions
High Response RateHigh Response Rate
Manageable toxicities: Manageable toxicities: – Neutropenia and thrombocytopenia were the only Gr3 Neutropenia and thrombocytopenia were the only Gr3
eventsevents
Basis for Basis for VISTAVISTA Phase III trial (n=680): VMP vs MPPhase III trial (n=680): VMP vs MP
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
HOW TO IMPROVE VMP ?HOW TO IMPROVE VMP ?
V-MPTV-MPTBortezomib + Melphalan + Bortezomib + Melphalan + Prednisone + ThalidomidePrednisone + Thalidomide
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
Protocol GIMEMA-MM-03-05Protocol GIMEMA-MM-03-05
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
A PHASE III, MULTI-CENTER, RANDOMIZED OPEN LABEL A PHASE III, MULTI-CENTER, RANDOMIZED OPEN LABEL STUDY OF VELCADE, MELPHALAN, PREDNISONE AND STUDY OF VELCADE, MELPHALAN, PREDNISONE AND
THALIDOMIDE (V-MPT)THALIDOMIDE (V-MPT)
VersusVersus
VELCADE, MELPHALAN, PREDNISONE (V-MP) VELCADE, MELPHALAN, PREDNISONE (V-MP)
IN ELDERLY UNTREATED MULTIPLE MYELOMA IN ELDERLY UNTREATED MULTIPLE MYELOMA PATIENTSPATIENTS
Combinations therapies in Multiple MyelomaCombinations therapies in Multiple Myeloma
Bortezomib + Thalidomide Bortezomib + Thalidomide +/- cytotoxic drugs+/- cytotoxic drugs
M-C
OM
PO
NE
NT
induction
High-dose
relapse
remission
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
Take home message
• Combinations increase response rate
• Frontline therapy
+ New Drugs
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
GIMEMA: Italian Myeloma Network1. ALESSANDRIA1. ALESSANDRIA Levis, BaraldiLevis, Baraldi
2. ANCONA2. ANCONA Leoni, OffidaniLeoni, Offidani
3. AOSTA3. AOSTA Di VitoDi Vito
4. ASCOLI PICENO4. ASCOLI PICENO Galieni, BigazziGalieni, Bigazzi
5. ASTI5. ASTI Scassa, CampaScassa, Campa
6. AVELLINO6. AVELLINO Cantore, VolpeCantore, Volpe
7. AVIANO7. AVIANO Tirelli, RupoloTirelli, Rupolo
8. BARI8. BARI Dammacco, LautaDammacco, Lauta
9. BARI9. BARI LisoLiso
10. BERGAMO10. BERGAMO Barbui, GalliBarbui, Galli
11. BIELLA11. BIELLA TonsoTonso
12. 12. BOLOGNA Cavo, TosiCavo, Tosi
13. BOLZANO13. BOLZANO PescostaPescosta
14. BRA14. BRA Vanni, StefaniVanni, Stefani
15. BRESCIA15. BRESCIA Rossi, CrippaRossi, Crippa
16. CAGLIARI16. CAGLIARI Angelucci, CarubelliAngelucci, Carubelli
17. CAGLIARI17. CAGLIARI MantovaniMantovani
18. CAMPOBASSO18. CAMPOBASSO StortiStorti
19. CANDIOLO19. CANDIOLO Aglietta, CapaldiAglietta, Capaldi
20. CATANIA20. CATANIA Giustolisi,Di RaimondoGiustolisi,Di Raimondo
21. CATANZARO21. CATANZARO PiroPiro
22. CATTOLICA22. CATTOLICA Pasquini Pasquini
23. CESENA23. CESENA GuardigniGuardigni
24. CHIOGGIA24. CHIOGGIA BattistaBattista
25. CIRIE'25. CIRIE' Freilone, BeggiattoFreilone, Beggiatto
26. COSENZA26. COSENZA MorabitoMorabito
27. CREMONA27. CREMONA Passalacqua, MorandiPassalacqua, Morandi
28. CREMONA28. CREMONA MorandiMorandi
29. CUNEO29. CUNEO Gallamini, GrassoGallamini, Grasso
30. FIRENZE30. FIRENZE Bosi/NozzoliBosi/Nozzoli
31. FOGGIA31. FOGGIA Ferrandina Ferrandina
32. FOGGIA Monaco
33. FORLI’ Amadori, Gentilini
34. GALLARATE Ciambelli
35. GENOVA Gobbi, Canepa
36. GENOVA Carella
37. LATINA Zapone
38. LECCE Pavone
39. MATERA Ciancio
40. MESSINA Brugiatelli, Mamone
41. MESSINA Musolino
42. MILANO Corradini, Montefusco
43. MILANO Morra
44. MILANO Bregni
45. MODENA Narni
46. MONTEFIASC. Montanaro, Niscola
49. MONZA Pogliani, Rossini
50. NAPOLI Rotoli,Catalano
51. NAPOLI Ferrara
52. NOCERA INF. D’Arco, Califano
53. NOVARA Gaidano, Rossi
54. NUORO Latte, Palmas
55. ORBASSANO Saglio, Guglielmelli
56. PADOVA Semenzato, Zambello
57. PALERMO Mirto, Cangialosi
58. PARMA Rizzoli, Giuliani
59. PAVIA Lazzarino, Corso
60. PERUGIA Liberati, Nunzi
61. PESARO Visani, Leopardi
62. PESCARA Fioritoni, Spadano
63. PIACENZA Cavanna, Lazzaro
64. PINEROLO Griso
65. PISA Petrini/Benedetti
66. POTENZA Ricciuti, Vertone
67. RAVENNA Zaccaria, Molinari
68. REGGIO CAL. Nobile, Callea
69. REGGIO EMILIA Gugliotta,Masini
70. RIMINI Pasquini, Fattori
71. ROMA Annino, Bongarzoni
72. ROMA Andriani
73. ROMA 1 Foà, Petrucci
74. ROMA Cattolica Leone, De Stefano
75. ROMA R.Elena Petti, Pisani
76. ROMA S. Camillo Majolino, De Rosa
77. ROMA T. Vergata Amadori, Caravita, i
78. ROZZANO Santoro, Nozza
79. S. G. ROTONDO Musto, Merla
80. SASSARI Longinotti, Dore
81. SIENA Lauria, Gozzetti
82. TARANTO Mazza, Casulli
83. TORINO 1 Boccadoro, Palumbo
84. TORINO 2 Gallo, Pregno
85. TORINO MAURIZ. Poccardi, Gottardi
86. TORINO S. VITO Marinone, Ficara
87. TREVISO Foscolo, Gherlinzoni
88. TRIESTE De Sabbata
89. UDINE Fanin, Patriarca
90. VARESE Pinotti
91. VENEZIA Chisesi
92. VERBANIA Montanara, Luraschi
93. VERONA Pizzolo, Meneghini
94. VICENZA Rodeghiero, Elice