Disease control with
with
active long-term treatment
Antonio Palumbo
Department of Oncology,
University of Turin,
Italy
Faculty disclosure information
Consultant: No
Grant/Research Support: No
Speakers Bureau: Janssen-Cilag, Celgene
Major Stock
Stock Shareholder: No
No
Overall survival is improving:
the Mayo Clinic experience
Overall survival in 5-year intervals from the time of diagnosis
100
19711976
1977 1982
80
19831988
19891994
ts(%)
60
19952000
t
2001 2006
40
20012006
Patien
20
0 0
20
40
60
80
100
120
140
Time (months)
Kumar SK, et al. Blood. 2008;111:2516-20.
Goals of myeloma therapy in 2009
· Id
Improved overalll
i
surv val
· Sustained disease control
· Acceptable toxicity
· Ability to work and to continue family life
Longer treatment duration is associated
with prolonged overall survival
Subgroup analysis of MM-009 and MM-010: Len + Dex
Effect of longer duration of Len + Dex in responding patients
10 months
> 10 months
p value
(n = 223)
(n = 98)
Median treatment duration
6.6
17.6
(range), months
(0.225.0)
(12.325.6)
Median OS, months
23.4
NR
< 0.0001
(> 31.6 months)
2-Year survival rate, %
48.4
93.8
< 0.0001
Every effort should be made to manage adverse events so that
patients can remain on treatment
San Miguel JF, et al. Blood. 2008;112:[abstract 3702];
NR = not reached.
updated data presented at ASH, 2008.
Kinetics of neutropenia and
thrombocytopenia during treatment
treatment
Oral melphalan, prednisone, and lenalidomide (MPR) for newly diagnosed MM
Neutropenia
/L*6 4,000
0
3,000
s×1 2,000
trophil 1,000
eu
0
N
C1
C2
C3
C4
C5
C6
C7
C8
C9 M2 M4 M6
Thrombocytopenia
/L*
250
9
200
10
×
150
100
50
lateletsP
0
C1
C2
C3
C4
C5
C6
C7
C8
C9
M2 M4
M6
Treatment cycle
* Mean ± SE.
Palumbo A, et al. Blood. 2008;112:[abstract 2768]; updated data presented at ASH, 2008.
Haematological adverse events decline
during treatment
treatment
Haematological events in patients with relapsed/refractory MM
treated with Len
Len + Dex
4.0
4.0
Grade 3: Len + Dex
Grade 3: Len + Dex
3.5
Grade 3: Dex alone
3.5
Grade 3: Dex alone
-months)
-months)
Grade 4: Len + Dex
Grade 4: Len + Dex
n
n
30
3.0
30
3.0
Grade 4: Dex alone
Grade 4: Dex alone
perso
2.5
perso 2.5
2.0
2.0
er100
er100
(p
(p
1.5
1.5
1.0
1.0
ehazard
ehazard
0.5
0.5
verag
verag
0
0
A
A
190
181270
361450
541630
190
181270
361450
541630
91180
271360
451540
91180
271360
451540
Time (days)
Time (days)
Treatment interruptions and dose reductions also declined during follow-up
Ishak J, et al. Blood. 2008;112:[abstract 3708]; updated data presented at ASH, 2008.
Long-term treatment with novel agents and
management of haematological adverse events
Adverse event
Action
On the first day of a new cycle
Withhold treatment until grade 1
Platelets < 75,000/L or
Reinitiate at lower dose*
ANC < 1,500/L
During the cycle
Start G-CSF
ANC < 500/
500/ L
Withhold treatment
treatment
Reinitiate next cycle at lower dose*
During the cycle
Withhold treatment and anticoagulation
Platelets < 2550,000/L
Reinitiate next cycle at lower dose*
*Lenalidomide: 5 mg dose reduction.
Palumbo A, et al. Blood Rev. [Epub ahead of print 2008 Sep 5].
Thromboembolism: risk factors
Diagnosis
Large tumour mass
Concomitant chemotherapy, including
doxorubicin
high-dose dexamethasone (> 160 mg/month)
erythropoietin use
Previous VTE, central
central venous
venous catheter
Age (> 55 years), immobilization
Infection
Factor V Leiden mutations +
Protein C deficiency +
Protein S deficiency +
Antithrombin III deficiency +
Palumbo A, et al. Leukemia. 2008;22:414-23.
VTE is manageable and decreases
after the
the first 4 cycles of therapy
ECOG-E4A03 study
MM-009 and MM-010:
subgroup analysis
30
Len + high-dose Dex
4.0
Average hazard of DVT over time
25.6
Len + low-dose Dex
3.5
)
Grade 3: Len + Dex
%
n-months)
30
(%
3.0
Gd
Grade 3: Dex onl
20.2
y
20
Grade 4: Len + Dex
VTE
2.5
perso
Grade 4: Dex Only
2.0
ceof
11
er100
11.4
(p
1.5
10
8.2
Inciden
1.0
ehazard
0.5
0
verag
0
A
Cycles 14
Later in the
190
181270
361450
541630
91180
271360
451540
tr
treat
ea m
tment
ent cour
course
Time (d
(days)
High-dose Dex itself is a major VTE risk factor
Ishak J, et al. Blood. 2008;112:[abstract 3708]; udated data presented at ASH, 2008.
Jacobus S, et al. Blood. 2008;112:[abstract 1740].
Management of VTE risk
in MM treatment
· Guidelines for prop
pphylaxis
prophylaxis is necessary if patient has any VTE risk factors upon
treatment with Len + Dex
Dex
low-dose aspirin (81100 mg) for low-risk patients receiving
low-dose Dex
proph
pp ylactic-dose LMWH for high-risk
g
patients
p
low-dose warfarin not recommended
Palumbo A, et al. Leukemia. 2008;22:414-23.
MM-009 and MM-010: Len + Dex prolongs
survival and improves renal function
MM-009 and MM-010: prospective subgroup analysis
of MM patients with renal insufficiency
insufficiency
Renal impairment
Efficacy
None
Mild
Moderate
Severe
(CLCr > 80 ml/min)
(50 CLCr 80 ml/min)
(30 CLCr < 50 ml/min)
(CLCr < 30 ml/min)
Number of patients
158
125
42
16
Median TTP, months
11.3
12.1
11.4
7.9
Median PFS, months
11.1
10.6
11.1
7.8
Overall survival,
NR
34.7
30.4
18.6*
months
* p < 0.01 compared with patients with no renal impairment.
Of 174 patients with renal insufficiency, 68% (119) had improvement in their
renal function by at least one level within 4 months,
as assessed by p
ypeak creatinine clearance rate
CLCr = creatinine clearance rate;
NR = not reached.
Weber D, et al. J Clin Oncol. 2008;26:[abstract 8542].
Dose recommendations for lenalidomide
in MM patients with
with renal
renal impairment
Renal impairment
Dose
Mild
25 mg every day
(CL
Cr
50 mL/min)
Moderate
10 mg every day*
(30 CLCr < 50 mL/min)
Severe
15 mg
(CLCr < 30 mL/min, not requiring dialysis)
every 48 hours
End-stage renal disease
5 mg
mg every
every day**
(CLCr < 30 mL/min, requiring dialysis)
* The dose may be increased to 15 mg daily after 2 cycles if patient has no
response to treatment.
** On dialysis days the dose should be administered after dialysis.
Revlimid SmPC; updated January 2009.
Peripheral neuropathy: risk factors1
Pre-existing peripheral neuropathy at time of diagnosis2
routine clinical diagnosis:
313%3
routine clinical diagnosis:
313%
detailed neurological testing:
48% small-fibre neuropathy4
electrophysiology and histopathology: ~35%
Age
Comorbid conditions, e.g. diabetes
Previous exposure to
to a neurotoxic antimyeloma agent
1. Richardson PG, et al. J Clin Oncol. 2006;24:3113-20.
2. Dispenzieri A, Kyle RA. Best Pract Res Clin Haematol. 2005;18:673-88.
3. Richardson PG. Blood. 2005;106:[abstract 2548].
4. Silberman J, Lonial S. Hematol Oncol. 2008;26:55-65.
Risk of onset of peripheral neuropathy with
bortezomib increases
increases over time
100
90
80
5 cycles
y
8 cycles
y
70
(%)
60
All grades
50
ents
40
Pati
30
20
Grade 3 or 4
10
0
0
1020
3040
5060
Cumulative calculated dose (mg/m2)
Richardson PG, et al. Br J Haematol. [Epub ahead of print 2009 Jan 16].
Management of peripheral neuropathy
in treatment of MM
· Prevention is
is difficult
difficult
· Treatment of medication-related peripheral neuropathy
has disappointin
pp
g results
treatment approach consists mainly of discontinuation and
dose modification (SmPC guidelines)
weekly administration reduces
reduces incidence of
of neuropathy to
approximately 5%
· Peripheral neuropathy one of the most frequent
non-haematological side-effects of treatment can
have debilitating consequences for the patient
Tariman JD, et al. Clin J Oncol Nurs. 2008;12(3 Suppl):29-36.
The chronic, progressive nature of MM
requires long-
long term, active treatment
treatment
· Appropriate management of
of adverse events is important
to avoid dose reductions and discontinuations, to ensure
greatest efficacy of treatment
better disease control
prolonged overall survival
· The risk
risk of
of haematological adverse events and DVT
declines during the treatment course, while the risk of
peripheral neuropathy increases
· Long-term use of lenalidomide is not limited by
peripheral neuropathy