Gammapatie monoclonali e mieloma multiplo
Varese, 14 novembre 2011
Terapia del paziente non candidato a trapianto
Luca Baldini
UO Ematologia 1-CTMO
Università degli studi di Milano
Fondazione IRCCS Cà Granda OM Policlinico, Milano
Elderly patients with MM
MM is predominantly a disease of the elderly
In the US, two-thirds of pts is 65 years old
ASL TORINO: 902.000 people
Median age at diagnosis:
65-75 years
31%
36%
69.4 years
25-64 years
33%
75-101 years
Regione Piemonte, Assessorato Sanità 2006,15
Major milestones in Multiple Myeloma Therapy
Single vs
double ASCT
Other CCT
regimens = MP
Melph-Pdn
1962
ASCT
HDMelphalan
1986
Quality of response
Bortezomib
Thal
1996
1999
Lenalidomide
2003
2005
PF survival
Overall survival
LB– UNIMI
LESSON FROM NEW AGENTS IN MM
• Role of CR
• New toxicities
• Different subsets of elderly pts
LESSON FROM NEW AGENTS IN MM
• Role of CR
•Different subsets of elderly pts
•New toxicities
What disease response is best?
Depth of response
Time to progression
Treatment initiation
MR
PR
VGPR
nCR
CR
sCR
iCR
mCR
Time
Depth of response is related to TTP
Niesvizky et al. Br J Haematol 2008; 143(1): 46-53; Harousseau et al. Blood 2009; 114(15): 3139-3146
Chanan-Khan et al. J Clin Oncol 2010; 28(15): 2612-2624
CR correlates with survival
International MyelomaWorking Group criteria (2009)
Retrospective analysis of three randomized studies
from GIMEMA and HOVON (n=1175; median age: 72 yrs)
MP (n=332), MPT (n=332), VMP (n=257), or VMPT-VT (n=254)
CR
CR (195)
VGPR
VGPR (212)
PR
PFS
PR (397)
p<0.001
OS
p<0.001
Median follow-up: 29 months
Gay et al. Blood 2011; 117(11): 3025-3031
CR associata a miglior PFS e OS
anche nei pazienti >75 anni
CR
VGPR
PR
3y PFS
79%
24%
23%
3y OS
88%
65%
57%
3y PFS
3y OS
Gay et
al. Blood
2010
Gay et al. ASH
2010
(Abs
1949)
La miglior qualità della risposta
è associata a miglior QoL
Progressive
disease
Study details
Stable
disease
•
n=292 newly diagnosed MM
•
Prospective comparison:
Continuous prednisone + VMCP
Partial
response
Intermittent prednisone + VMCP
•
Complete
response
0
20
40
60
80
Collection of quality of life
data using EORTC QLQ-C30
100
Quality of life score
Ludwig et al. IMW 2007; (Abs 1103)
LESSON FROM NEW AGENTS IN MM
• Role of CR
• New toxicities
• Different subsets of elderly pts
Summary Table of Selected
Therapy-Related Adverse Effects
Thalidomide[1]
Peripheral
Neuropathy
DVT
Lenalidomide[2]
Bortezomib[3]
(20-30%);
grade 3-4: 4-8%;
painful,
usuallyreversible
(50%):
grade 3-4: 5-8%;
may be irreversible
More with dex (4-15%)
More with dex (7%)
Neutropenia
Neutropenia (21%),
thrombocytopenia (10%)
anemia
Thrombocytopenia
(20%)
(70%)
(38%)
Myelosuppression
Hypotension
Fatigue, weakness
Sedation
Rash
GI Disturbance
(30%)
Constipation
(50%)
Constipation (39%)
diarrhea (29%)
Nausea and
vomiting,
diarrhea (8%)
1. Thalidomide [package insert]. 2. Lenalidomide [package insert]. 3. Bortezomib [package insert].
4. Orlowski RZ, et al. J Clin Oncol. 2007;25:3892-3901.
L. Baldini -UniMI
LESSON FROM NEW AGENTS IN MM
• Role of CR
• New toxicities
• Different subsets of elderly pts
Improvements in Survival by Age
10-Yr Relative Survival (%)
Period Estimates of 10-Yr Survival by Major Age Groups
in Defined Calendar Periods
50
45
40
35
30
25
20
15
10
5
0
Age, yrs
< 50
50-59
60-69
70-79
80+
19841986
19871989
19901992
19931995
Years
19961998
19992001
20022004
Improvements in survival for elderly patients expected with
longer follow-up of ongoing trials
Brenner H, et al. Blood. 2008;111:2521-2526.
Management of elderly patients
The NCCN guidelines on treating older adults with cancer
recommend using Comprehensive Geriatric Assesment tools to
asses the patient’s likely tolerance of treatment by formally
assessing:
- comorbidities,
- functional status
- geriatric syndromes
- polypharmacy,nutrition
- socioeconomic status and personal preferences
Toxicity
Comorbidities
Depth of
response
Niesvizky R et al. Oncology 24:3; March 2010
Len + High- or Low-Dose Dex (E4A03 trial)
Low-dose Dex = 40 mg/day PO, on Days 1, 8, 15, 22
High-dose Dex = 40 mg/day PO, on
Days 1-4, 9-12, 17-20
High Dose Low Dose
P Value
Best overall response, %
81
70
.009
≥ VGPR, %
50
40
.040
OVERALL SURVIVAL
Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.
Nel paziente > 75 aa, il raggiungimento della
miglior risposta possibile è auspicabile, ma
altri parametri devono essere considerati
TTNT (time to next treatment): è il tempo
dall’inizio di un trattamento all’inizio del
successivo
TFI (treatment free interval): è il tempo dalla
fine di un trattamento all’inizio del
successivo
QoL
TWiST (time without symptoms disease or
toxicity related)
LB– UNIMI
Terapia con nuovi
agenti a dose
ridotta o terapia
convenzionale
Terapia con nuovi
agenti
a dose piena
Expanding treatment options in front-line
therapy for elderly myeloma pts
MP/CTX +
novel agents
• MPT (GIMEMA, IFM, NMSG,
HOVON, Turkish study
group)
• CTD (MRC Myeloma IX)
• VMP (VISTA, PETHEMA,
GIMEMA)
Dex +
novel agents
• Bortezomib/Dex-based
(UPFRONT study)
• Thal/Dex-based
(ECOG, Celgene 003,
CEMSG, MRC Myeloma IX)
• VMPT-VT (GIMEMA)
• Len/Dex (ECOG, SWOG
others)
• VMP-VT/VP (PETHEMA)
• Len/Bortezomib/Dex
(DFCI)
• MPR-R (GIMEMA)
CONVENTIONAL THERAPY
MP, Dex, VAD or VAD-like regimens
• ORR ~ 50%
• CR < 5%
• Median DFS: 18 mos
• Median OS: 3 yrs
LB– MM 30.10.08
Farmaci concessi dal SSN in Italia per la
terapia di prima linea del paziente non
ASCT candidabile
MP, HCTX, VAD
MP+Thalidomide (MPT)
Frontline therapy in elderly pts (FDA, EMEA,AIFA
march 2009)
MP+Bortezomib (MPV)
Frontline therapy in elderly pts (FDA and EMEA 2008,
AIFA july 2009)
L. Baldini -UniMI
ALKILATING +
NOVEL AGENTS
without
maintenance
MP vs MPT Studies
Patient Characteristics and MPT Regimens
GIMEMA[1,2]
IFM 9999-06[3]
IFM 0101-01[4]
HOVON[6]
232 (113)
NMSG[5]
362 (182)
331 (167)
447 (125)
Median
72
69
78.5
75 (mean)
72
Range
60-85
65-75
76-91
49-92
N/A
5
8
7
30
4
Cycles, n
6
12
12
Until
plateau
Until
plateau
M dosing
4 mg/m2
Days 1-7
0.25 mg/kg
Days 1-4
0.2 mg/kg
Days 1-4
0.25 mg/kg
Days 1-4
0.25 mg/kg
Days 1-5
100
Up to 400
100
Up to 400
200
+
-
-
+
+
Patients, n (MPT)
301 (152)
Age, yrs
WHO grade 3/4, %
MPT regimen
Thal dosing, mg/day
Maintenance
1. Palumbo A, et al. Lancet. 2006; 367:825-831.
2. Palumbo A, et al. Blood. 2008;112:3107-3114.
3. Facon T, et al. Lancet. 2007;370:1209-1218.
4. Hulin C, et al. JCO 2009, 27: 3664-3670.
5. Waage A, et al. Blood 2010, 116: 1405-12
6. Wijermans P, et al. JCO 2010, 28:3160-66
Summary of MPT phase III trials in the upfront setting
Regimen
n. Pts
(median FU)
GIMEMA
Thal/MP
MP
IFM 99-06
Thal/MP
MP
MEL 100
IFM 01-01
Thal/MP
MP
NMSG
Thal/MP
MP
HOVON
Thal/MP
MP
129 (18)
126 (15)
191
124
121
(
1
5
)
113
116
182
181
165 (nr)
168 (nr)
CR
(%)
CR+VGPR
(%)
PFS
(mos)
OS
(mos)
15
2
29
11
21.8
14.5
45
47.6
13
(51) 2
18
47
7
‘’
27.5
17.8
19.4
51.6
33.2
38.3
21
7
24.1
18.5
44.3
29.1
(47)
(42)
7
1
13
3
4
2
23
7
23
8
15
14
15
11
29
32
40
31
Reference
Palumbo et al.
Blood 2008;
112:3107-14
.0006
.028
Facon, et al.
Lancet 2007;
370:1209–18
Hulin, et al.
JCO 2009;
27:3664-3670
Waage A et al.
Blood 2010
116(9):1405-12
Wijermans P, et
al. JCO 2010,
28:3160-66
Toxicities of THAL combined
with melphalan in phase III trials
MPT
(n=167)
Palumbo et al.
(GIMEMA)
MPT
(n=124)
Facon et al
(IFM)
MPT
(n=113)
Hulin et al.
(IFM)
- Infections
10
17
n./a.
- Neutropenia
22
41
20
- DVT
12
12
7
- Neuropathy
8
6
2
Thal Discontinuation /
Treatment withdrawal (%)
46.5*
45*
53*
Toxicity grade 3-4 (%)
* Due to adverse events
LB– UNIMI
Valutazione del rischio trombotico
in pazienti trattati con talidomide
Fattori di rischio
individuali
Pregressa trombosi
Trombofilia ereditaria
Fattori di rischio
associati alla terapia
Desametasone ad alte dosi
Doxorubicina
Obesità
Polichemioterapia
CVC
Comorbidità (diabete, infezioni..)
Interventi chirurgici
Fattori di rischio
associati al mieloma
Trombosi nel MM: ~5%
LB– UNIMI
Profilassi antitrombotica in
pazienti trattati con IMiD
Aspirina
Se ≤1 FR individuali o associati al mieloma
Eparina a basso peso molecolare
Se ≥2 FR individuali o associati al mieloma
Se talidomide + HD dexa, doxorubicina, poli-CT
Palumbo et al, Leukemia 2008; Palumbo et al, EHA 2008
LB– UNIMI
CTD vs MP : MRC Myeloma IX
Phase III, Study in Elderly Patients with Newly
Diagnosed MM
849 pts (median age 73 yrs; 57-89)
RANDOMIZATION
P<.001
CTD
MP
CTX 500 mg po,
po, days
1,8,and 15;
THAL
THAL 5050-200 mg/day;
Dex 20 mg/day days 11-4
and 1515-18 q 4 wk
Response, %
100
80
63.8
60
13
40
17
32.6
2.4
1.7
20
28.6
33.8
0
CTD (n = 426) MP (n = 423)
RANDOMIZATION
PR
VGPR
CR
No differences in terms of OS and PFS
–Thal
+Thal
100 mg/day
(36 and 12 mos)
Correlation with quality of response and
cytogenetic profile)
VTE 16% vs 4.5%
Morgan et al. Blood, 2011
VISTA - Velcade as Initial Standard Therapy in
newly diagnose multiple myeloma (> 65 yrs or
not transplant eligible): Assessment with
melphalan and prednisone
54 weeks
682 pts
Bort 1.3 mg/m2 IV on
Days 1, 4, 8, 11, 22, 25,
29, 32 during first
four 6-week cycles +
MP*
(n = 344)
Bort 1.3 mg/m2 IV on
Days 1, 8, 22, 29 for
five 6-week cycles +
MP*
(n = 344)
Melphalan (9 mg/sm) and Prednisone (60 mg/sm) on days 1-4
for nine 6-week cycles
(n = 338)
DOSE/INTENSITY OF BORTEZOMIB: 52 doses/54 wks
Primary end point: TTP
San Miguel J, NEJM 2008; 359:906
LB– Unimi
VISTA: response rates and TTP
Responses
Time to progression
74%
PR
VGPR
CR
39%
Event-free patients (%)
p < 0.001
100
80
60
40
Median TTP
MPV: 24 months
MP: 16.6 months
HR 0.48; p < 0.001
20
0
0
3
6
9
12 15
18
21 24
27
Time (months)
San Miguel JF, et al. N Engl J Med. 2008;359:906-17.
VISTA: overall survival
Surviving patients (%)
3-year OS rates: MPV 68.5%, MP 54.0%
100
80
60
40
Median follow-up: 36.7 months
Median OS
MPV: not reached (109 deaths)
MP: 43.1 months (148 deaths)
HR 0.653 (95% CI 0.508–0.840); p = 0.0008
20
0
0
3
6
9
12 15 18 21 24 27 30 33 36 39 42 45 48 51
Time (months)
Mateos MV, et al. J Clin Oncol. 2010;28:2259-66.
VISTA - Adverse events
VMP (N=340)
AE, %
MP (N=337)
Grade 3
Grade 4
Grade 3
Grade 4
Neutropenia
30
10
23
15
Thrombocytopenia
20
17
16
14
Anemia
16
3
20
8
GI
19
1
5
<1
Peripheral sensory neuropathy
13
<1
0
0
Fatigue
7
1
2
0
Asthenia
6
<1
3
0
Pneumonia
5
2
4
1
Herpes zoster
3
0
2
0
Overall rate of peripheral sensory neuropathy with VMP was 44%, including 14% grade 1, 17% grade 2
At data cutcut-off 74% of peripheral neuropathy (PN) events had resolved to baseline (56%) or
decreased by at least one toxicity grade (18%) in a median of 2 months
Herpes zoster was more frequent with VMP (13% vs 4%); rate with VMP only 3% among patients
receiving antiviral prophylaxis
Rate of DVT was low and similar with VMP vs MP (1% vs 2%)
LB– UNIMI
Raccomandazioni per la gestione della
neuropatia da Bortezomib
Segni e sintomi di PN
Azione
Grado 1 (parestesie e/o perdita
dei riflessi senza dolore nè deficit
funzionali)
Se bisettimanale passare a
monosettimanale; se
monosettimanale ridurre di un livello
Grado 2 (non interferisce con lo
svolgimento delle normali attività
quotidiane)
Se bisettimanale passare a
monosettimanale; se monosettimanale
ridurre di un livello o sospendere
temporaneamente. Se migliora riprendere
monosettimanale con dose ridotta
a 1 mg/m2
Grado 3 e 4 (disabilitante)
Sospendere definitivamente
La presenza di dolore neuropatico innalza di 1 grado
Riduzione dose livello 1 =: 1 mg/sm; livello 2= 0.7 mg/sm
Delforge et al, Lancet Oncol 2010
Bortezomib planned dose: 67.6 mg/sm
mg/sm;; administreded dose: 38.5 mg/sm
mg/sm
Bortezomib planned dose: 36.4 mg/sm
mg/sm;; administreded dose: na
Bortezomib planned dose: 46.8 mg/sm
mg/sm;; administreded dose: 40 mg/smn
mg/smn
MM-015: phase 3 trial of MPR vs MP for longterm control in newly diagnosed MM
51 centres in Europe, Australia, and Israel (N = 459)
R
A
N
D
O
M
I
Z
A
T
I
O
N
Cycles (28-day) 1–9
Cycles 10+
MPR-R
Melphalan 0.18 mg/kg, days 1–4
Prednisone 2 mg/kg, days 1–4
Lenalidomide 10 mg/day p.o., days 1–21
Lenalidomide
continued
MPR
Melphalan 0.18 mg/kg, days 1–4
Prednisone 2 mg/kg, days 1–4
Lenalidomide 10 mg/day p.o., days 1–21
MPSecondary comparison
Melphalan
0.18
MPR-R
vsmg/kg,
MPR days 1–4
Prednisone
mg/kg,
Addition of 2MPR
armdays
per 1–4
EMEA
Placebo
days advice
1–21
10 mg/day
days 1–21
Placebo
P
R
O
G
R
E
S
S
I
O
N
Len
(25 mg/day)
± Dex
Placebo
Double-blind treatment phase
Open-label extension and
follow-up phase
Stratification by age (≤ 75 vs > 75 years) and ISS stage (1, 2, or 3)
Palumbo A, et al. Blood. 2010;116:[abstract 622]. Updated data presented at ASH 2010.
MM-015: response rates significantly
higher with MPR vs MP
Best overall response*
ORR (≥ PR) (%)
CR** (%)
≥ VGPR*** (%)
Median time to first response
(months)
MPR
(n = 153)
MP
(n = 154)
67
50
13
4
32
12
2
3
*As measured using EBMT criteria.1
**Immunofixation negative with or without bone marrow confirmation.
***VGPR: > 90% reduction in M protein.
Palumbo A, et al. Blood. 2010;116:[abstract 622].
1. Bladé J, et al. Br J Haematol. 1998;102:1115-23.
MM-015: MPR vs MP progressionfree survival
100
Median PFS
Patients (%)
75
MPR
14 months
MP
13 months
50
25
p = 0.153
0
0
5
10
15
20
25
30
Time (months)
Median follow-up 25 months
35
40
*Analysis based on data up to May 2010.
Palumbo A, et al. Blood. 2010;116:[abstract 622]. Updated data presented at ASH 2010.
Treatment – Initial 9 cycles
MPR
MP
65 - 75 years of age
17
10
> 75 years of age
34
16
65 - 75 years of age
88
97
> 75 years of age
56
97
Discontinuation rate (%)
▪
Cumulative dose intensity (%) ▪▪
▪ Discontinuation due to AEs or withdrawal of consent
▪▪ Cumulative dose intensity of melphalan and lenalidomide/placebo
DEX + NOVEL
AGENTS
Lenalidomide + High (RD) vs Low-Dose Dex (Rd)
in Elderly Patients with Newly Diagnosed MM:
ECOG (E4A03 phase III study)
Four 28-day cycles
445 pts
Median age 66 yrs
(51-88)
RD Arm A
Lenalidomide 25 mg/day orally
on Days 1-21 +
Dexamethasone 40 mg orally
on Days 1-4, 9-12, 17-20
(Dex tot 480)
(n = 223)
Rd Arm B
Lenalidomide 25 mg/day orally
on Days 1-21 +
Dexamethasone 40 mg orally
on Days 1, 8, 15, 22
(Dex tot 160)
(n = 222)
CR/PR
< PR
ASCT or RD/Rd
or no further
therapy
CR/PR
4 cycles thal + dex
LB– MM UniMi
Phase III ECOG Trial: RD vs Rd
After 4 induction cycles:
– ≥ VGPR 51% with RD vs 40% with Rd
– ≥ PR 81% with RD vs 70% with Rd
PFS: 24-26 months
– (P = .08 log-rank; P = .04 Pepe-Fleming)
OS: 75% at 3 years
– Although initial findings suggested better OS with Rd; OS
at 3 years identical for both treatment arms
– (P = .46 log-rank; P = .01 Pepe-Fleming)
Rajkumar SV, et al. Lancet Oncol. 2009
Novel agents in combination as primary treatment
(without maintenance)
Median
PFS or
TTP (mos)
Study
n
Median
age, years
MPT1
IFM 99-06
125
69
47
76
MPT2,3
MPT vs MP
167
72
29
69
22
MPV4,5
VISTA
337
71
41
74
TTP: 24
MPR6
MPR
153
71
33
67
14
ECOG-E4A03
≥ 65 years
222
65
40
70
26
MRC Myeloma IX
NA
73
40
50
12
Rd7
CTDa8,9
≥VGPR, %
≥PR, %
28
1. Facon T, et al. Lancet. 2007;370:1209-18. 2. Palumbo A, et al. Lancet. 2006;367:825-31. 3. Palumbo A, et al. Blood. 2008;112:3107-14. 4. San Miguel JF, et al.
N Engl J Med. 2008;359:906-17. 5. Mateos MV, et al. Blood. 2009;114:[abstract 3859]. 6. Palumbo A, et al. Blood. 2009;114:[abstract 613]. 7. Rajkumar SV, et al.
Lancet Oncol. 2009. 8. Morgan GJ, et al. Blood. 2007;110:[abstract 3593]. 9. Owen RG, et al. Presented at IMW 2009 [abstract 547].
Outcomes from randomized phase 3 trials in elderly NDMM
Median
age
CR rate
%
Median
PS
Median
OS, mos
Stop rate,
%
69-78
10-23
15-28
26-52
40-55
VMP (VISTA)
71
30
na
nr
34
VMP (Palumbo)
71
24
23
nr
17
Rd (Rajkumar)
66
4
25
nr
19
VMPT
(Palumbo)
71
38
nr
nr
23
MPR-R
(Palumbo)
71
16
nr
nr
13
CTDa (Morgan)
73
13
13
33
NA
Regimen
MPT (5 studies)
Novel agents as primary treatment:
safety
IFM
MPT
VISTA
MPV
GIMEMA
MPR
ECOG
Rd
Neutropenia
48
40
52
20
Thrombocytopenia
14
37
24
5
Anaemia
14
19
5
7
Neuropathy
6
13
0
2
DVT
12
1
5
12
Infection
10
7
9.5
9
Herpes zoster
2.5
3
Grade 3 or 4
adverse events, %
NR
NR
Moreau P, et al. Blood Rev. 2008;22:303-9.
Rajkumar SV, et al. Lancet Oncol. [Epub ahead of print 2009 Oct 21.]
OPEN QUESTIONS ABOUT NEW
AGENTS IN MM
• Role of CR
• Different subsets of elderly pts
• New toxicities
• Fixed doses or continuos therapy
• Identification of the best synergistic effect
• New-new agents
Approach to MM cells control
Progression free Survival
TARGET OF EFFICACY
MM
cells
Citostatici convenzionali
• Improvement
of quality of response
• Improvement orofIFN/Dex
OS
Continuous terapy
(continuous
ther. vs ther. at relapse)
Nuovi farmaci ± CT
Overall Survival
time
Phase III Study of Bortezomib, Melphalan,
Prednisone (VMP) ± Thalidomide (VMPT) in elderly
patients with Newly Diagnosed MM: GIMEMA Trial
Newly
diagnosed
symptomatic
MM
≥65 yr or
<65 yr and not
transplanteligible
(N=393)
R
A
N
D
O
M
I
Z
A
T
I
O
N
VMP
Bortezomib 1.3 mg/m2 IV
days 1,8,15,22*
Melphalan 9 mg/m2 and
prednisone 60 mg/m2 days 1–4
NO MAINTENANCE
VMPT
Bortezomib 1.3 mg/m2 IV
days 1,8,15,22*
Melphalan 9 mg/m2 and
prednisone 60 mg/m2 days 1–4
Thalidomide 50 mg/d continuously
MAINTENANCE
Bortezomib 1.3 mg/m2 IV
days 1,15
Thalidomide 50 mg/day
9 × 5-wk cycles in both arms
Until relapse
*61 VMP patients and 70 VMPT patients were treated with biweekly infusions of bortezomib
Palumbo A, et al. J Clin Oncol. 2010;28:5101-9.
GIMEMA (MPVT-VT vs MPV): efficacy
Patients (%)
Response
MPVT-VT
(n = 250)
MPV
(n = 253)
p value
CR
42
24
< 0.0001
≥ VGPR
64
50
0.001
≥ PR
90
81
0.007
OS at 3 years
85
80
0.35
Palumbo A, et al. J Clin Oncol. 2010;28:5101-9.
GIMEMA (MPVT-VT vs MPV):
PFS and TTNT
Median follow-up: 32 months
Progression-free survival
Time to next therapy
41% reduced risk of progression
48% reduced risk of progression
3-year PFS
MPVT
51%
37.2 months
MPVT
70%
Not reached
MPV
32%
27.4 months
MPV
51%
37.6 months
1.00
0.75
Patients (%)
Patients (%)
1.00
3-year TTNT Median TTNT
Median PFS
0.50
0.25
HR 0.59
p < 0.0001
0.75
0.50
HR 0.52
p < 0.0001
0.25
0.00
0.00
0
10
20 30 40
Time (months)
50
60
0
10
20 30 40
Time (months)
50
60
Palumbo A, et al. J Clin Oncol. 2010;28:5101-9.
PETHEMA/GEM study phase 3 trial of MPV
and VTP in elderly patients with
previously untreated MM
Untreated MM;
age > 65 years
(N = 253)
R
A
N
D
O
M
I
Z
A
T
I
O
N
MPV (n = 130)
Bortezomib 1.3 mg/m2 for one
6-week cycle, days 1, 4, 8, 11,
22, 25, 29, 32; then for five
5-week cycles, days 1, 8, 15, 22
Melphalan 9 mg/m2 and
Prednisone 60 mg/m2, days 1–4
of each cycle
VTP (n = 130)
Bortezomib as above,
continuous Thalidomide
100 mg/day,
Prednisone as above
Maximum 6 cycles
Maintenance
Bortezomib 1.3 mg/m2,
days 1, 4, 8, 11 every
3 months
Prednisone 50 mg
every other day
Maintenance
Bortezomib 1.3 mg/m2,
days 1, 4, 8, 11 every
3 months
Thalidomide 50 mg/day
Up 3 years
Mateos MV, et al. Lancet Oncology. 2010;11:934-41.
VMP vs VTP → VT vs VP in Elderly Newly
Diagnosed Myeloma Patients: Responses
Outcome Following Induction, %
VMP
(n = 130)
VTP
(n = 130)
CR (if negative)
20
27
CR (if positive)
12
10
PR
48
46
MR
10
6
8
11
VT
(n = 91)
VP
(n = 87)
44
15
39
2
39
16
44
1
After a median follow-up of 32 months from first
ORR
80
81
randomization
SD
• median PFS for all patients was 31 months
• median TTP was 35 months
• 3-year OS was 70%
• no significant differences between the MPV and
Outcome Following
Maintenance Therapy, %
CR/nCR
CR (if negative)
CR (if positive)
PR
MR
VTP groups in PFS (p = 0.1) and 3-year OS (p =
0.3)
Overall CR rate (if negative) increased from 23% following induction to 42% after maintenance
Mateos MV, et al. Lancet Oncol. 2010;11:934-941.
Toxicity of Maintenance in Elderly MM Patients
Grade 3/4 adverse events significantly increased in VMPT → VT vs VMP arms
(Neutropenia (P = .02); Cardiologic (P = .04); Deep vein thrombosis/pulmonary
embolism (P = .05)
More patients in VMPT → VT vs VMP arm discontinued treatment due to
adverse events: 21% vs 16%
Palumbo A, et al. J Clin Oncol. 2010;28:5101-9.
MPV treatment produced more haematological adverse events than VTP
(particularly grade 3 or worse neutropenia and thrombocytopenia)
VTP was associated with severe cardiac complications
(11 patients (8%) compared with none in those receiving MPV)
Rate of infections was higher with MPV than with VTP
Mateos MV, et al. Lancet Oncology. 2010;11:934-41.
MM-015: phase 3 trial of MPR vs MP for longterm control in newly diagnosed MM
51 centres in Europe, Australia, and Israel (N = 459)
R
A
N
D
O
M
I
Z
A
T
I
O
N
Cycles (28-day) 1–9
Cycles 10+
MPR-R
Melphalan 0.18 mg/kg, days 1–4
Prednisone 2 mg/kg, days 1–4
Lenalidomide 10 mg/day p.o., days 1–21
Lenalidomide
continued
MPR
Melphalan 0.18 mg/kg, days 1–4
Prednisone 2 mg/kg, days 1–4
Lenalidomide 10 mg/day p.o., days 1–21
MPSecondary comparison
Melphalan
0.18
MPR-R
vsmg/kg,
MPR days 1–4
Prednisone
mg/kg,
Addition of 2MPR
armdays
per 1–4
EMEA
Placebo
days advice
1–21
10 mg/day
days 1–21
Placebo
P
R
O
G
R
E
S
S
I
O
N
Len
(25 mg/day)
± Dex
Placebo
Double-blind treatment phase
Open-label extension and
follow-up phase
Stratification by age (≤ 75 vs > 75 years) and ISS stage (1, 2, or 3)
Palumbo A, et al. Blood. 2010;116:[abstract 622]. Updated data presented at ASH 2010.
MM-015: response rates significantly
higher with MPR-R vs MP
Best overall response*
ORR (≥ PR) (%)
MPR-R
(n = 152)
MP
(n = 154)
p value
(MPR-R vs MP)
77
50
< 0.001
CR** (%)
16
4
< 0.001
≥ VGPR*** (%)
32
12
< 0.001
2
3
< 0.001
Median time to first response
(months)
*As measured using EBMT criteria.1
**Immunofixation negative with or without bone marrow confirmation.
***VGPR: > 90% reduction in M protein.
Palumbo A, et al. Blood. 2010;116:[abstract 622].
1. Bladé J, et al. Br J Haematol. 1998;102:1115-23.
MM-015: MPR-R significantly improved
progression-free survival
100
Patients (%)
Median PFS
low incidence of adverse events
MPR-R 31 months
75during lenalidomide continuous treatment
MPR
14 months
13 months
MP
but
50
p < 10-7
maintenance
therapy should performed only in
25
clinical trials!
p = 0.153
0
0
5
10
15
20
25
30
Time (months)
Median follow-up 25 months
35
40
*Analysis based on data up to May 2010.
Palumbo A, et al. Blood. 2010;116:[abstract 622]. Updated data presented at ASH 2010.
COSA è CAMBIATO CON LE NUOVE ASSOCIAZIONI?
La THAL e il Bortezomib si potenziano in associazione con MP
Il patner ideale per la Len non sembra essere MP ma il Dex/dex
La scelta dell’uno vs l’altro dipende da considerazioni specifiche sul singolo
paziente (PS/comorbidità, rischio genetico, PNP all’esordio etc)
Le dosi dei nuovi agenti devono essere aggiustate in relazione all’età
Non ci sono dati a favore che l’utilizzo contemporaneo dei nuovi agenti
possa comportare ad un miglioramento della risposta in grado di incisìdere
sulla OS rispetto ad un uso sequenziale volto ad ottenere il massimo da ogni
singolo agente
Mantenimento/Extended therapy migliora la qualità della risposta e la PFS.
Non ci sono dati a favore di un incremento della OS (soprattutto vs un
trattamento alla recidiva). Il mantenimento con Bortezomib o Thal aumentano
la tossicità. MPR-R: secondo tumore?
VULNERABILITY OF ELDERLY PATIENTS
Frailty grade
Description
Active, energetic patients, who exercise
weakness
, poor
endurance, weight
regularly
or occasionally
physical activity
, slow
gaitactive
speed
Patients not
regularly
beyond
routinely walking
Very
►fit Fraility:
loss, low
Moderately fit
Patients who can perform limited activities
concurrent
presence
of
≥
2
but
yet
do
not
need
help
from
other
At least 2 comorbidities in US: people
medically diagnosed diseases.
Vulnerable
► Comorbidity:
- 60-69 yrs: 35%
in who
M need
andhelp
45%
in F
Patients
for household
Mildly frail
tasks (shopping, walking several blocks,
managing
finances,
and
- 80 yrs
: 53%
in
Mtheir
and
70%
inmedications)
F to
► Disability
: difficulty
in activities
essential
Patients whocare,
need partial
help for their
independent living (personal
household
tasks)
Moderately frail
Severely frail
personal care (dressing, bathing, toileting,
eating)
Patients completely dependent on other
people for their personal care
Palumbo et al, Blood 2011
Report of European
Myeloma Network
(EMN) on
personalized
therapy in MM
according to age
and vulnerability
Palumbo et al, Blood oct 2011
CR, PFS and OS
CR and PFS
QoL
►
►
►
PROPOSAL OF THERAPEUTIC ALGORITHM
FOR PTS NOT CANDIDATE FOR ASCT
< 75 yrs or fit
> 75 yrs or frail
Specific complications
NO
YES
LowLow-dose MPT
LowLow-dose Bz ± MP
MP
LowLow-dose Dex
Low dose Len/
Len/Dex
CDT
CtxCtx-Pdn
MPT
Renal:
Renal: BzBz-based
MPV
Thrombophilic status,
cardiovascular events:
events: BzBz-based
CTD
Rd
MPRMPR-R ?
Poor genetic risk:
risk: BzBz-based
History of PN: LenLen-based
Future Directions (Continued)
?
Tuning of tested
combinations
Newer combinations….
Novel agent sequences (second
generation PIs, HDAC inhibitors, other
small molecules, 3rd generation IMiDs,
MoAbs)
Tailored approach to therapy:
• Identify groups of pts in whom combinations are
required versus pts in whom doublets and/or
sequences should be used
• Use of GEP, Proteomics
• Risk adaptation
?
In the Absence of Data…
Quality
of Life
Response
CLINICAL TRIALS!!!!!!
and Risk Based Therapy
IMWG response criteria
Durie et al., Leukemia 2006
sCR: CR più normale rapporto FLC, assenza di cellule clonali midollari
all’analisi citofluorimetrica ed immunoistochimica
CR: IF negativa nel siero e nelle urine, scomparsa di localizzazioni tessutali
da plasmacitoma e <5% di plasmacellule midollari
VGPR: negatività all’elettroforesi o riduzione di della CM sierica ≥ 90% e BJ
proteinuria <100 mg/24h
PR: riduzione della CM sierica ≥50% e della BJ ≥ 90% o < 200 mg/24h; nei
MM non secernenti, riduzione ≥ 50% del rapporto FLC e della
plasmocitosi midollare ≥ 50% (partendo da un infiltrato iniziale ≥ 30%;
nei plasmacitomi solitari, riduzione ≥ 50% delle dimensioni
SD: se non soddisfatti i criteri della CR, VGPR, PR e della progressione (non
criterio di risposta; utile per calcolare TTP)
LB– UNIMI
IMiDs, bortezomib
Dex
Bortezomib
Hsp90 inh HDAC inh
Alkylators
Anthracyclines
Mitochondria
NFκB
Cytochrome-c
Caspase-8
Smac
Transcriptional
changes
Caspase 9
CaspaseCaspase-3
Proteasome
Aggresome
PARP
TUMOR CELL DEATH
TUMOR CELL DEATH
The Future: Synergistic anti-MM activity…
Proteasome Inhibitor/IMiD-based Novel Agent Combos