Microsoft PowerPoint - ASH2009_Mateos

QuiRedex
A Multicenter, Randomised, Open-label, Phase III Study
of Lenalidomide/Dexamethasone versus Therapeutic
Abstention in high-risk Smoldering MM
MV Mateos, L López-Corraz, MT Hernández, J de la Rubia, JJ Lahuerta, P Giraldo, J Bargay, L Rosiñol,
A Oriol, J García-Laraña, l Palomera, F de Arriba, F Prósper, ML Martino, AI Teruel, J Hernández, G
Estevez, M Mariz, A Alegre, JL Guzman, N Quintana, JL García, JF San Miguel.
On behalf of Spanish Myeloma Group (PETHEMA/GEM)

Smoldering Multiple Myeloma
· M- protein in serum 30 g/L AND/OR
· Bone Marrow clonal plasma cells 10%
No CRAB (hypercalcemia, anemia, bone lesions, renal impairment) or symptoms
1%
3%
10%
IMWG Br J Haematol 2003; 21:749-57
Kyle R. N Engl J Med 2007; 356:2582-90

Smoldering Multiple Myeloma: prognostic factors
Type of monoclonal protein (IgA)
Presence and type of urinary light chain (>50mg/24h)
Abnormal MR Imaging studies (MRI)
Evolving MM
Abnormal sFLC ratio
Serum level of Monoclonal Component (>3g/dl)
Extent and pattern of BM infiltration (PCs>10%)
Aberrant PC by immunophenotype ( 95%)
Reduction in uninvolved immunoglobulins
Alexanian et al, 1988; Hjorth et al, 1993; Dimopoulos et al, 1993;2000; Facon et al, 1995; Moulopoulos et al, 1995;
Weber et al, 1997; Rosiñol et al, 2003; Cesana et al, 2002; Perez-Persona, 2007; Kyle et al, 2007; Dispenzieri et al, 2008

Smoldering Multiple Myeloma: PCs BM infiltration and
Serum M-component level
TTP: 2 y
TTP: 8 y
TTP: 19 y
Group 1: PCBM 10% + MC 3g/dl
Group 2: PCBM 10% + MC < 3g/dl
Group 3: PCBM < 10% + MC 3g/dl
Kyle R. N Engl J Med 2007; 356:2582-90

Smoldering Multiple Myeloma: Aberrant PCs by
immunophenotype plus immunoparesis
1,0
5 years
p= 0.003
>95% aPC/BMPC + paresis
n= 39 (28 progr.)
0,8
82%
Median 23 months
0,6
>95% aPC/BMPC or
paresis
progression
n= 22 (10 progr.)
0,4
to
Median 73 months
42%
Time%
8%
0,2
No adverse factors
n= 28 (1 progr.)
Median not reached
0,0
0
24
48
72
96
120
Months
Pérez E. Blood 2007; 110:2586-92

Smoldering Multiple Myeloma: Management
· The standard of care is close follow-up every few months
· Therapeutic abstention
· Several attemps to treat smoldering MM:
- MP1 vs abstention (50 pts): No benefit for MP arm
- Thal2 (31 pts): PR 34%; 2y-PFS: 63%; high toxicity
- Thal3 (76 pts): PR 25%; achieving PR or better shorter time
to Myeloma therapy
1Hjorth M. Eur J Haematol. 1993 Feb;50(2):95-102
2Rajkumar V. Leukemia 2003; 17: 775-9
3Barlogie B. Blood 2008; 112(8): 31223125

QuiRedex
QuiRedex: High-risk smoldering MM
PCs BM 10% plus M-protein 30 g/L
or
PCs BM 10% or M-protein 30 g/L
but BM aPC/nPC > 95% plus immunoparesis
Time elapsed from diagnosis to inclusion not superior to 5 years
No CRAB (hypercalcemia, anemia, bone lesions, renal impairment) or symptoms

QuiRedex
Schedule of therapy
Treatment arm
Control arm
Lenalidomide
Induction:
25 mg/daily during 21d every 28 d
Nine 4-wks cycles
Dexamethasone
Therapeutic Abstention
20 mg D1-D4 and D12-D15 every 28 d
Lenalidomide
Maintenance
Therapeutic Abstention
10 mg/daily during 21 d
every 2 months
Randomization according to: diagnosis in the last 6 months
diagnosis more than 6 months

QuiRedex
Objectives
Primary objective
Time to progression to symptomatic MM
Secondary objectives
Response rates
Duration of response
Progression Free Survival, Overall Survival
Safety and tolerability

QuiRedex
Biological Objectives
· Phenotypic and functional studies of T and NK lymphocytes and
dendritic cells both pre and post- treatment with Lendex
· Gene Expression Profile on tumor cells to identify profiles indicating
sensitiviy/resistance to Lendex, profiles indicating progression to symptMM
in therap abst arm and also on BM microenvironment cells to know the
effect of Lendex
· Bone markers
· Abnormalities in differentiation of myeloid cells by flow cytometry

Study Status
QuiRedex
120
114
120
106
97
100
88
79
94
80
72
85
82
63
75
54
60
65
45
57
53
36
40
45
27
42
19
35
20
9
25
5
13
0
nov-07
jan-08
mar-08 may-08
jul-08
sep-08 nov-08
jan-09
mar-09 may-09
jul-09
sep-09 nov-09 dec-09
All data were monitored by an external CRO
An IDMC was designed to validate inclusion criteria and time to progression

QuiRedex
Baseline patients' characteristics (n:94)
Lendex
Therap abst
(n:47)
(n:47)
Mean (Median) Age, yr
61 (39-89)
65 (42-80)
IgG / IgA / light chain, %
66 /32/ 3
60 / 37/ 2
PCsBM infiltration, mean %
20%
21%
Serum MC, mean
32
30
Urine MC, mean
0.65
0.31
Time from diagnosis, median
9 (1-60)
6 (1-60)
High PCBM+ High MC
59
54
aPC95% plus immunoparesis
41
46
Rbdel/t(4;14)/t(14;16)/p53, %
42/ 11/ 5/ 3
36/ 14 / 5/ 9
No significant differences

QuiRedex
Lendex: Response rate after induction on ITT (n:40)
Median number of cycles: 4 (1-9)
ORR: 81%; sCR: 3%, CR: 11%, VGPR: 16%, PR: 51%, SD: 19%
VGPR: 30%
*IMWG criteria

QuiRedex
Lendex: Response rate in patients who completed the
9 induction cycles (n:23)
ORR: 91%; sCR: 4%, CR: 17%, VGPR: 17%, PR: 52%, SD: 9%
VGPR: 38%
*IMWG criteria

QuiRedex
QuiRedex: Time to Progression (n:94)
Median follow-up: 14 m (1-24)
1 pt IC withdrawal during the 1st cycle
1 pt discontinuation after the 8th cycle
Lendex
1,0
0,8
No treatment
0,6
Progressions in abstention arm (n=16)
Median TTP: 19.3 m
6 pts: lytic lesions
0,4
3 pts: lytic lesions plus anemia
1 pt:lytic lesions renal failure & hypercalcemia
0,2
5 pts: anemia
1pt: PD due to a rapid increase of BJ prot from 4,5g/24h
p<0,0001
to 9g/24h in 1 month
0,0
0
3
6
9
12
15
18
21
24

QuiRedex
QuiRedex: Overall Survival (n:94)
Median follow-up: 14 m (1-24)
1.0
Lendex
0.8
No treatment
0.6
0.4
0.2
Lendex: 100% at 2 y
No treat: 96% at 2 y
0.0
0
3
6
9
12
15
18
21
24

QuiRedex
Lendex:Toxicity profile (n:47)
G1-2
G3
Anemia, n (%)
8 (17%)
1 (2,6%)
Neutropenia, n (%)
10 (21%)
-
Thrombocytopenia, n (%)
5 (11%)
-
Asthenia
7 (15%)
2 (4.5%)
Anorexia
4 (9%)
Pancreatitis
-
1 (2%)
Constipation
5 (11%)
4 (9%)
Diarrhea
3 (6%)
1 (2%)
Rash
8 (17%)
1 (2%)
Paresthesias
2 (4%)
Infection
9 (19%)
DVT*
3 (6%)

QuiRedex
Lendex:Toxicity profile (n:47)
G1
G2
G3
Anemia, n (%)
7 (15%)
1 (2%)
1 (2%)
Neutropenia, n (%)
3 (6%)
7 (15%)
-
Thrombocytopenia, n (%)
8 (17%)
-
-
Asthenia
6 (13%)
1 (2%)
2 (4%)
Anorexia
4 (9%)
Pancreatitis
-
1 (2%)
Constipation
5 (11%)
4 (9%)
Diarrhea
1 (2%)
2 (4%)
1 (2%)
Rash
5 (10%)
4 (8%)
1 (2%)
Paresthesias
2 (4%)
Infection
7 (14%)
2 (4%)
DVT*
3 (6%)
DVT prophylaxis with Aspirin (100mg) in 1 pt, oral anticoagulation in 1 pt with low INR levels and
no px in the other one

QuiRedex
Lendex: Safety profile (n:47)
Related-SAEs, n (%)
-5 Patients (11%)
- In 3 Dex-related :G-I bleeding, delirium, glaucoma
- In 2 Len-related: Infection, pancreatitis
Pts discontinuing due to SAEs, n (%)**
- 1 pt (2%) discontinued due to delirium
Dose reductions, n(%)
- Lenalidomide
From 25 to 15 mg (induction)
4 (8%)
G3 diarrhea (1 pt), G3 asthenia (2 pts), Pancreatitis G3 (1 pt)
- Dexamethasone
From 20 to 10 mg
1 (2%)
G1 diarrhea and G1 tremor (1 pt)
No deaths have been reported
**Four additional pts discontinued Lendex due to withdrawal of IC

QuiRedex
QuiRedex: Summary
Promising efficacy results
·
ITT analysis: ORR 81%; VGPR 30%
·
Patients who have completed the 9-induction cycles: ORR 91%; VGPR 38%
Time to Progression to symptomatic MM
·
Median TTP in therapeutic abst arm: 19 months
·
16 out of 47 pts in therapeutic abst arm have already progressed, and 10 out
of them presenting bone lessions
Toxicity profile
·
Toxicity was manageable. No G4 hemat/non-hemat AEs were reported
·
Low frequency of G3 AEs

Acknowledgments
Investigators including patients in the Spanish Myeloma Group's
trials, and most of all, the patients!