mieloma multiplo tumore delle plasmacellule producono immunoglobuline vivono nelle ossa divisione...
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MIELOMA MULTIPLOMIELOMA MULTIPLO
tumore delle plasmacelluletumore delle plasmacellule
producono immunoglobulineproducono immunoglobuline
vivono nelle ossavivono nelle ossa
DIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALY
Multiple myeloma• uncontrolled proliferation of Ig secreting plasma cells
– most commonly IgG (57%), IgA (21%) or light chain only (18%)• twice as common in men as women• and in blacks as whites• 1% of all cancers
– 2% in african americans• incurable• median survival 3 years
• few therapeutic advances since the introduction of melphalan (Bergsagel, 1962)
Myeloma bone pathology
Multiple Myeloma (MM)
• B-cell neoplasia, characterized by the expansion of plasma cells producing an abnormal monoclonal immunoglobulin
• 21,500 new cases yearly in Europe
• Median age at diagnosis: 65 years
• incurable disease
MM – Impact for PatientsConsequences of MM include:
• Painful osteolytic bone lesions
• Bone marrow infiltration, causing anemia, fatigue, and immunodeficiency, with an increased risk of serious infections
• The abnormal proteins may cause renal dysfunction or kidney failure
Bruno B, Rotta M, and Boccadoro M, Lancet Oncology 2004
IL-1IL-1
OAFOAF
IL-6IL-6
MIELOMA MULTIPLOMIELOMA MULTIPLO
hepatocytehepatocyte
CRPCRP
OSTEOCLASTOSTEOCLAST
DIVISIONE UNIVERSITARIA DI DIVISIONE UNIVERSITARIA DI EMATOLOGIAEMATOLOGIAAZIENDA OSPEDALIERA S. GIOVANNI AZIENDA OSPEDALIERA S. GIOVANNI BATTISTABATTISTATORINO, ITALYTORINO, ITALY
MIELOMA MULTIPLOMIELOMA MULTIPLO
malattia dell'anzianomalattia dell'anziano
5/100.000/pazienti/anno5/100.000/pazienti/anno
350 pazienti/anno in Piemonte350 pazienti/anno in Piemonte
età media alla diagnosi 70 annietà media alla diagnosi 70 anni
DIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALY
Serum protein electrophoresis (SPEP)
albumin
Elevated total protein suggests hypergammaglobulinemia
Total protein= Albumin + Globulins
Serum protein electrophoresis (SPEP)
albumin
Elevated total protein suggests hypergammaglobulinemia
Total protein= Albumin + Globulins
Quantitative immunoglobulins
measures amount of IgM, IgG and IgA
in myeloma, typically see “reciprocal depression” of uninvolved Igs
Serum protein electrophoresis (SPEP)
albumin
Immunoeletrophoresis
Serum protein electrophoresis (SPEP)
albumin
Immunoeletrophoresis
SP
Immunofixation
Serum protein electrophoresis (SPEP)
SP
Immunofixation
IgG 57%IgA 21%IgD 1%IgM or IgE almost neverLight chain only 18%
Serum protein electrophoresis (SPEP)
SP
Immunofixation
IgG 57%IgA 21%IgD 1%IgM or IgE almost neverLight chain only 18%
M-spike stands for Monoclonal, not IgM
Serum protein electrophoresis (SPEP)
SP
Immunofixation
IgG 57%IgA 21%IgD 1%IgM or IgE almost neverLight chain only 18%
M-spike stands for Monoclonal, not IgM
IgM, IgG and IgA are all gamma-globulins
Serum protein electrophoresis (SPEP)
SP
Immunofixation
IgG 57%IgA 21%IgD 1%IgM or IgE almost neverLight chain only 18%
M-spike stands for Monoclonal, not IgM
Light chains (Bence-Jones proteins) are not detected in the serum, because of their low molecular weight, they are secreted in the urine
IgM, IgG and IgA are all gamma-globulins
Table 1 Multiple myeloma* Diagnostic criteria
1 Monoclonal plasma cells in the bone marrow 10% and/or presence of a biopsy-proven plasmacytoma2 Monoclonal protein present in the serum and/or urinea3 Myeloma-related organ dysfunction (1 or more)
[C] Calcium elevation in the blood (serum calcium >10.5 mg/l or upper limit of normal)[R] Renal insufficiency (serum creatinine >2mg/dl)[A] Anemia (hemoglobin o10 g/dl or 2 gonormal)[B] Lytic bone lesions or osteoporosisc
Myeloma - clinical features
bone pain - often with loss of height
constitutional - weakness, fatigue and weight loss
anemia - responds to erythropoeitin
renal disease -renal tubular dysfunction
susceptibility to infections - neutropenia, hypogammaglobulinemia)
hypercalcemia - myeloma cells secrete osteoclast activating factors
hyperviscosity - 2 % with myeloma, 50 % with macroglobulinemia
neurologic dysfunction - spinal cord or nerve root compression
Myeloma staging system cells x 10 /m
12 2
MedianSurvival(months)
Stage I No anemia >60 <0.6No hypercalcemiano more than one bony lesionlow M protein
Stage II in between I and III 41 0.6-1.2
Stage III Anemia 23 >1.2hypercalcemiaadvanced lytic bone diseasehigh M protein
Principles of treatment• no evidence that early treatment prolongs survival• wait for symptoms, or evidence of disease
progression to start treatment• supportive measures are critically important
– drink 3l of fluids daily– treat infections promptly– prophylactic bisphosphonates reduce skeletal cmplications– anemia responds to erythropoeitin
Causes of death in multiple myeloma
• Progressive myeloma 45%
• Sepsis 25%
• Renal failure 10%
• Other (old age) 20%
Treatment course
Asymptomatic
MGUSStable MM
Years Months Days
Treatment course
Asymptomatic
MGUSStable MM
Symptomatic
Years Months Days
Treatments
M protein
Treatment course
Asymptomatic
MGUSStable MM
Symptomatic Acute
PancytopeniaPlasma cell leukemia
Years Months Days
Treatments
M protein
MIELOMA MULTIPLOMIELOMA MULTIPLO
trattato con blande chemioterapietrattato con blande chemioterapie
parzialmente chemiosensibileparzialmente chemiosensibile
il tumore si riduce ma dopo breve il tumore si riduce ma dopo breve intervallo riprende a crescereintervallo riprende a crescere
DIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALY
MIELOMA MULTIPLOMIELOMA MULTIPLO
chemioterapiachemioterapia
Melphalan e Prednisone (MP)Melphalan e Prednisone (MP)
(Alexanian, 1969)(Alexanian, 1969)
DIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALY
MIELOMA MULTIPLOMIELOMA MULTIPLO
100100
5050
36 mesi36 mesi
sopravvivenzasopravvivenza
DIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALY
MULTIPLE MYELOMAMULTIPLE MYELOMA
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
MIELOMA MULTIPLOMIELOMA MULTIPLO
relazione dose-rispostarelazione dose-risposta
ALTA-DOSE =ALTA-DOSE = + risposte complete+ risposte complete
+ lunga sopravvivenza+ lunga sopravvivenza
DIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALY
RIDUZIONE DELLA TOSSICITA'RIDUZIONE DELLA TOSSICITA'DELLE TERAPIE AD ALTE DOSIDELLE TERAPIE AD ALTE DOSI
FATTORI DI CRESCITAFATTORI DI CRESCITA
CELLULE STAMINALI PERIFERICHECELLULE STAMINALI PERIFERICHE
tossicità comparabile alla terapia tossicità comparabile alla terapia convenzionaleconvenzionale
possibilità di trattare pazienti anzianipossibilità di trattare pazienti anziani
alte percentuali di risposte completealte percentuali di risposte complete
A PROSPECTIVE, RANDOMIZED TRIAL OF A PROSPECTIVE, RANDOMIZED TRIAL OF AUTOLOGOUS BONE MARROW AUTOLOGOUS BONE MARROW
TRANSPLANTATION AND CHEMOTHERAPY TRANSPLANTATION AND CHEMOTHERAPY IN MULTIPLE MYELOMAIN MULTIPLE MYELOMA
Sopravvivenza a 5 anniSopravvivenza a 5 anni 52% trapianto52% trapianto
12% convenzionale12% convenzionale
Attal, et al., NEJM, 1996Attal, et al., NEJM, 1996
0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1
0 10 20 30 40 50 60 70
EFS TOT
MEL100
MP
Months
% o
f p
atie
nt s
p<0.001
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1
0 10 20 30 40 50 60 70 80
OS TOT
Months
% o
f p
atie
nt s MEL100
MP
p<0.005
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
5555 6060 6565 7070
MULTIPLE MYELOMAMULTIPLE MYELOMAMULTIPLE MYELOMAMULTIPLE MYELOMA
DIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALY
AGEAGE
AGE AT DIAGNOSISAGE AT DIAGNOSIS
DIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALY
5555 6060 6565 7070
MULTIPLE MYELOMAMULTIPLE MYELOMAMULTIPLE MYELOMAMULTIPLE MYELOMA
DIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALY
AGEAGE
AGE AT DIAGNOSISAGE AT DIAGNOSIS
HIGH-DOSEHIGH-DOSE CONVENTIONALCONVENTIONAL
survivalsurvival%%
yearsyears
100100
DIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALY
MALATTIA INCURABILEMALATTIA INCURABILE
Relapsed Disease• Transient Response to Therapy• Survival 1-3 years
Multiple myelomaMultiple myeloma
Diagnosis• Survival 3-5 yrs
Relapsed andRefractory
• Resistant to all therapy• Universally fatal • Survival 6-9 months
Unmet
Medical Need
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
Bruno B, Rotta M, and Boccadoro M, Lancet Oncology 2004
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
Advancing Treatment Options in MM
Melphalan From 1990sMyeloablation +
ASCT
1999First reportthalidomide
1962 Prednisone +
melphalan
Thalidomide Pharmion licence
Aus/NZ 2003
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
VELCADE® US licence 2003VELCADE® EU positive
opinion 2004
scenario
MULTIPLE MYELOMA
+
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
ThalidomideThalidomide
Originally developed in 1950s as a Originally developed in 1950s as a treatment for insomnia and morning treatment for insomnia and morning sickness in pregnancysickness in pregnancy
Thalidomide is an immunomodulatory Thalidomide is an immunomodulatory agentagent
– Precise mechanism of action not yet understoodPrecise mechanism of action not yet understood
– Multiple actions, including anti-angiogenic effectsMultiple actions, including anti-angiogenic effects
• Anti-angiogenic effects of thalidomide provide the rationale for its use in MM
• Angiogenesis in bone marrow supports growth and development of MM cells
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
Antitumor activity of thalidomide
in refractory multiple myeloma.Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P,
Munshi N, Anaissie E, Wilson C, Dhodapkar M, Zeddis J, Barlogie B.
N Engl J Med 1999 Nov 18;341(21):1565-71Myeloma and Lymphoma Program, South Carolina Cancer Center, University of South Carolina, Columbia, USA.
BACKGROUND: Patients with myeloma who relapse after high-dose chemotherapy have few therapeutic options. Since increased bone marrow vascularity imparts a poor prognosis in myeloma, we evaluated the efficacy of thalidomide, which has antiangiogenic properties, in patients with refractory disease. METHODS: Eighty-four previously treated patients with refractory myeloma (76 with a relapse after high-dose chemotherapy) received oral thalidomide as a single agent for a median of 80 days (range, 2 to 465). The starting dose was 200 mg daily, and the dose was increased by 200 mg every two weeks until it reached 800 mg per day. Response was assessed on the basis of a reduction of the myeloma protein in serum or Bence Jones protein in urine that lasted for at least six weeks. RESULTS: The serum or urine levels of paraprotein were reduced by at least 90 percent in eight patients (two had a complete remission), at least 75 percent in six patients, at least 50 percent in seven patients, and at least 25 percent in six patients, for a total rate of response of 32 percent. Reductions in the paraprotein levels were apparent within two months in 78 percent of the patients with a response and were associated with decreased numbers of plasma cells in bone marrow and increased hemoglobin levels. The microvascular density of bone marrow did not change significantly in patients with a response. At least one third of the patients had mild or moderate constipation, weakness or fatigue, or somnolence. More severe adverse effects were infrequent (occurring in less than 10 percent of patients), and hematologic effects were rare. As of the most recent follow-up, 36 patients had died (30 with no response and 6 with a response). After 12 months of follow-up, Kaplan-Meier estimates of the
mean (+/-SE) rates of event-free survival and overall survival for all patients were 22+/-5 percent and 58+/-5 percent, respectively.
CONCLUSIONS: Thalidomide is active against advanced myeloma. It can induce marked and durable responses in some patients with multiple myeloma, including those who relapse after high-dose chemotherapy
Bruno B, Rotta M, and Boccadoro M, Lancet Oncology 2004, in Press DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIA
AZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
Thalidomide: mechanism of action ??
Humanmyeloma
Humanliver
Thal
Thal
Humanmyeloma
~
reduced
unchanged
Yaccoby et Al, Blood, 2002
“Thal metabolism required for its anti-myeloma efficacy”
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
MELPHALAN, PREDNISONE + MELPHALAN, PREDNISONE + THALIDOMIDE (MPT)THALIDOMIDE (MPT)
versus
MELPHALAN PREDNISONE (MP)MELPHALAN PREDNISONE (MP)
GRUPPO ITALIANO PER LO STUDIO DEL MIELOMA GRUPPO ITALIANO PER LO STUDIO DEL MIELOMA MULTIPLOMULTIPLO
INTERIM ANALYSIS INTERIM ANALYSIS
PROSPECTIVE RANDOMIZED TRIALPROSPECTIVE RANDOMIZED TRIAL
NEWLY DIAGNOSED PATIENTS, NEWLY DIAGNOSED PATIENTS, AGE > 65 YEARSAGE > 65 YEARS
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
ADVERSE EVENTS
Hematologic (%)
Constipation (%)
Neurologic (%)
Cardiac (%)
Cutaneous (%)
Infection (%)
Thromboemb.(%)
Early death (%)
3-4 1-2 WHO (grade)MPTMPT MPMP
3-4 1-2
29
28
32
17
15
14
18
7
9
3
2
10
35
-
11
3
3
12
25
-
-
4
-
1
19
5
4
5DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
RESPONSE TO THERAPYRESPONSE TO THERAPY
Dept. Hematology, University of Torino
0
20
40
60
80
100
MPT MP
PR (50-74)
PR (75-99)
CR + nCR
27.7%27.7%5.4%5.4%
33.8%33.8%
15.6%15.6%
13.3%13.3%
28%28%
77.1%77.1%
46.7%46.7%
% o
f R
esp
on
se%
of
Res
po
nse
EVENT-FREE SURVIVALEVENT-FREE SURVIVAL(median follow up 13.6 months)(median follow up 13.6 months)
0
0,2
0,4
0,6
0,8
1
0 5 10 15 20 25 30 35
MonthsMonths
Pro
po
rtio
nP
rop
ort
ion
p<0.001p<0.001
MPTMPT
MPMP
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
RESPONSE TO THERAPYRESPONSE TO THERAPY
10
20
30
% CR
MP Thal MP +Thal
27.7%27.7%
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
5% 3-5%
Revlimid ™ (lenalidomide)
(CC-5013)
Actimid™ (CC-4047)
NNHO O
O
NH2
NNH
O
O O
O
NH2
NNHO
O
O
O
Thalomid®
(thalidomide)
Bruno B, Rotta M, and Boccadoro M, Lancet Oncology 2004, in Press
The Proteasome: A Target for Novel Therapies
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
TNFR
TNF
IkBp65
p50
IkBp65
p50
PP
PUb
IkBp65
p50
PP
P
p50
p65IkB
PP
PUb
Protein kinases
NFkB-IkB complex
IkBP
P
PUb
Degradation of IkB by 26S proteasome
TNFR
TNF
IkBp65
p50
IkBp65
p50
PP
PUb
IkBp65
p50
PP
P
p50
p65IkB
PP
PUb
IkBP
P
PUb
NFkB binding site
Protein kinases
NFkB-IkB complex
p65p50
NFkB Nuclear translocation
NFkB Induced proteins
Block of programmed cell death
Increase in Cytokine production
Increase in adhesion molecules
Degradation of IkB by 26S proteasome
PS 341
TNFR
TNF
IkBp65
p50
IkBp65
p50
PP
PUb
IkBp65
p50
PP
P
p50
p65IkB
PP
PUb
NFkB binding site
Protein kinases
NFkB-IkB complex
p65p50
NFkB Nuclear translocation
NFkB Induced proteins
Block of programmed cell death
Increase in Cytokine production
Increase in adhesion molecules
Degradation of IkB by 26S proteasome
PS 341
TNFR
TNF
IkBp65
p50
IkBp65
p50
PP
PUb
IkBp65
p50
PP
P
p50
p65IkB
PP
PUb
NFkB binding site
Protein kinases
NFkB-IkB complex
NFkB Nuclear translocation
NFkB Induced proteins
Block of programmed cell death
Increase in Cytokine production
Increase in adhesion molecules
Degradation of IkB by 26S proteasome
PS 341p50
p65IkB
PP
PUb
p50
p65IkB
PP
PUb
TNFR
TNF
IkBp65
p50
IkBp65
p50
PP
PUb
IkBp65
p50
PP
P
p50
p65IkB
PP
PUb
Protein kinases
NFkB-IkB complex
NFkB Induced proteins
Block of programmed cell death
Increase in Cytokine production
Increase in adhesion molecules
Degradation of IkB by 26S proteasome
PS 341p50
p65IkB
PP
PUb
p50
p65IkB
PP
PUb
NFkB Nuclear translocation
TNFR
TNF
IkBp65
p50
IkBp65
p50
PP
PUb
IkBp65
p50
PP
P
p50
p65IkB
PP
PUb
Protein kinases
NFkB-IkB complex
NFkB Induced proteins
Block of programmed cell death
Increase in Cytokine production
Increase in adhesion molecules
Degradation of IkB by 26S proteasome
PS 341p50
p65IkB
PP
PUb
p50
p65IkB
PP
PUb
Antimyeloma effect
NFkB Nuclear translocation
SUMMIT (025):SUMMIT (025):A Phase II Study of VELCADEA Phase II Study of VELCADE™ (bortezomib) for ™ (bortezomib) for InjectionInjection in Patients With Relapsed and Refractory in Patients With Relapsed and Refractory Multiple MyelomaMultiple Myeloma
Paul G. Richardson,Paul G. Richardson,11 Bart Barlogie, Bart Barlogie,22 James Berenson, James Berenson,33 Seema Singhal, Seema Singhal,44 Ann Traynor, Ann Traynor,44 Sundar Sundar Jagannath,Jagannath,5 5 David Irwin,David Irwin,66 Vincent Rajkumar, Vincent Rajkumar,77 Gordan Srkalovic, Gordan Srkalovic,8 8 Melissa Alsina,Melissa Alsina,9 9 Raymond Alexanian,Raymond Alexanian,1010 David Siegel,David Siegel,1111 Robert Orlowski, Robert Orlowski,1212 David Kuter, David Kuter,13 13 Steven Limentani,Steven Limentani,1414 Dixie Esseltine, Dixie Esseltine,1515 Gretchen Gretchen Richards,Richards,1515 Michael Kauffman,Michael Kauffman,1515 Julian Adams, Julian Adams,1515 David P. Schenkein, David P. Schenkein,1515 and Kenneth C. Anderson and Kenneth C. Anderson11
11Dana-Farber Cancer Institute, Dana-Farber Cancer Institute, 22University of Arkansas, University of Arkansas, 33Cedars-Sinai Medical Center, Cedars-Sinai Medical Center, 44Northwestern University Medical Northwestern University Medical Center, Center, 55St Vincent’s Comprehensive Cancer Center, St Vincent’s Comprehensive Cancer Center, 66Alta Bates Cancer Center, Alta Bates Cancer Center, 77Mayo Clinic, Mayo Clinic, 88Cleveland Clinic Cleveland Clinic Foundation, Foundation, 99H. Lee Moffitt Cancer Center, H. Lee Moffitt Cancer Center, 1010M.D. Anderson Cancer Center, M.D. Anderson Cancer Center, 1111Carol G. Simon Cancer Center, Carol G. Simon Cancer Center, 1212University of University of North Carolina at Chapel Hill, North Carolina at Chapel Hill, 33Massachusetts General Hospital, Massachusetts General Hospital, 1414Charlotte Medical Clinic, Charlotte Medical Clinic, 1515Millennium Pharmaceuticals, Millennium Pharmaceuticals, IncInc
Median number of lines of Median number of lines of prior therapy = 6 (range prior therapy = 6 (range 2-15)2-15)
92% of patients received 92% of patients received at least 3 of the drug at least 3 of the drug therapies listed here therapies listed here (excluding stem cell (excluding stem cell transplant) transplant)
91% of patients were 91% of patients were refractory to the last prior refractory to the last prior therapytherapy
SUMMIT – Prior TherapySUMMIT – Prior Therapy
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%99.5%
92%
64%
81%83%
SUMMIT – Response Rates with SUMMIT – Response Rates with VELCADEVELCADE®® Alone Alone
35% response rate35% response rate
10% CR (IF+ and IF-)10% CR (IF+ and IF-)
28% CR+PR28% CR+PR
59% of patients SD59% of patients SDor betteror better
Mean duration of Mean duration of response 12 monthsresponse 12 months
4%
6%
18%
7%
24%
0%
5%
10%
15%
20%
25%35%
+-CR IF- CR IF+ PR MR SD
Prior treatment had no significant effect on response ratePrior treatment had no significant effect on response rate DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
Treatment plan Treatment plan –– APEX APEX
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 et al. NEJM 2005Richardson et al. NEJM 2005
APEX: Time to Progression (n=669)APEX: Time to Progression (n=669)78% improvement in median TTP with bortezomib78% improvement in median TTP with bortezomib
Median TTP: Bortezomib 6.2 months vs dexamethasone 3.5 monthsRichardson et al. NEJM 2005Richardson et al. NEJM 2005
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 et al. NEJM 2005Richardson et al. NEJM 2005
APEX: 1-year survival (n=669)APEX: 1-year survival (n=669)
41% decreased risk of death with bortezomib41% decreased risk of death with bortezomib
80%
66%
Richardson et al. NEJM 2005Richardson et al. NEJM 2005
APEX: Overall survival (n=669)APEX: Overall survival (n=669)
Median duration of follow-up 8.3 months
Richardson et al. NEJM 2005Richardson et al. NEJM 2005
ConclusionConclusion
Phase III APEX:Phase III APEX:
Bortezomib demonstrated superior efficacy to high-Bortezomib demonstrated superior efficacy to high-dose dexamethasone in relapsed MMdose dexamethasone in relapsed MM
– Significant TTP benefit (Significant TTP benefit (PP<.0001)<.0001)
– Response rate advantage (Response rate advantage (PP<.0001)<.0001)
– Superior 1-year survival (Superior 1-year survival (PP=.0005, HR=.53)=.0005, HR=.53)
– Superior overall survival (Superior overall survival (PP=.0013, HR=.57)=.0013, HR=.57)
Richardson et al. NEJM 2005Richardson et al. NEJM 2005
Most common adverse events from Most common adverse events from Phase I, SUMMIT, CREST and APEX trialsPhase I, SUMMIT, CREST and APEX trials
Adverse eventAdverse event Phase IPhase I11 SUMMITSUMMIT22 CRESTCREST33 APEXAPEX44
(%)(%) (%)(%) (%)(%) (%) (%)
Thrombocytopenia Thrombocytopenia 7474 4040 3030 35 35
FatigueFatigue 5959 4141 7070 42 42
NauseaNausea 5252 5555 5454 57 57
DiarrheaDiarrhea 3737 4444 4444 57 57
Constipation Constipation 3030 1616 3737 42 42
VomitingVomiting 3030 2727 NRNR 35 35
Peripheral neuropathyPeripheral neuropathy 1919 3131 4141 36 36
NR = not recorded11Orlowski Orlowski et alet al. . J Clin OncolJ Clin Oncol 2002;20:4420; 22Richardson Richardson et alet al. . N Engl J MedN Engl J Med 2003;348:2609; 2003;348:2609;
33Jagannath Jagannath et alet al. . Br J HematolBr J Hematol 2004;127:165; 2004;127:165; 44Richardson Richardson et alet al. ASH 2004 (abstract 336.5). ASH 2004 (abstract 336.5)
Toxicities were predictable and manageableToxicities were predictable and manageable
Combinations therapiesCombinations therapies in Multiple Myeloma in Multiple Myeloma
Bortezomib + Thalidomide Bortezomib + Thalidomide +/- cytotoxic drugs+/- cytotoxic drugs
M-C
OM
PO
NE
NT
induction
High dose
relapse
remission
Dana FarberDana FarberRichardsonRichardsonPhase II VELCADE alone in 1st linePhase II VELCADE alone in 1st line tx tx
CHU de CHU de NantesNantes
HarousseauHarousseauPhase II VELCADE + high-dose Phase II VELCADE + high-dose dexamthasone 1st line, pre-transplantdexamthasone 1st line, pre-transplant
LocationLocationPIPIStudyStudy
ECOG/CTEPECOG/CTEPDispenzieriDispenzieriPhase II VELCADE in high risk myeloma, 1st Phase II VELCADE in high risk myeloma, 1st lineline
U. MarylandU. MarylandBadrosBadrosPhase I/II VELCADE + DT-PACE, 1st linePhase I/II VELCADE + DT-PACE, 1st line
CALGBCALGBOrlowskiOrlowskiPhase II VELCADE + DoxilPhase II VELCADE + Doxil
U. ArkansasU. ArkansasBarlogieBarlogiePhase II VELCADE + Total Therapy III in high Phase II VELCADE + Total Therapy III in high risk myeloma 1st linerisk myeloma 1st line
Salick GroupSalick GroupJagannathJagannathPhase II VELCADE Phase II VELCADE monotxmonotxDex after 2 cycles for less than optimal Dex after 2 cycles for less than optimal responseresponse
Multiple Myeloma Studies in Development:Multiple Myeloma Studies in Development:Front LineFront Line
AUTOLOGOUS FIRST STEP
Thalidomide
Proteasomeinhibitors
MULTIPLE MYELOMA
Mini allo
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
Thalidomide Proteasomeinhibitors
MULTIPLE MYELOMA
DIVISIONE UNIVERSITARIA DI EMATOLOGIADIVISIONE UNIVERSITARIA DI EMATOLOGIAAZIENDA OSPEDALIERA SAN GIOVANNIAZIENDA OSPEDALIERA SAN GIOVANNITORINO, ITALYTORINO, ITALY
Chemo LanilomideLanilomide