What we know about myeloma in elderly
patients from trials and observational
studies?
Heinz Ludwig
Department of Medicine I
Center for Oncology, Hematology and Palliative Care
Wilhelminenhospital, Vienna, Austria
Ludwig© 2013
Goals of therapy in elderly patients
 Rapid symptom control
 Optimal quality of life
 Few and acceptable side effects
 Best possible quality of response
 Long PFS
 Long OS
 Cure ?
Ludwig© 2013
Drug combinations for elderly patients
Possible options
1-drug*
2 - drugs
3- drugs
4 - drugs
Dex
Bendamustine
+P
MPT
VMPT
Thal
VD
VMP
MP*
CTD
Thal-Dex
VTD
L-ldDex
*only exceptional cases
Most commonly used combinations contain 2-3 drugs
Ludwig© 2013
Characteristics of the Elderly Patient
Chronological age does not necessarily correlate with biological age
All three individuals are 70 years old
Fit
Minor morbidity
significant morbidity
The variation in biological fitness in a specific age cohort increases
with rising age, but the ‚biology‘ of myeloma cells does not vary with age
H. Ludwig 2013
Treatment of patients with multiple myeloma not
eligible for transplantation
Assess fraility
Fit
Unfit
Full
go
Slow
go
Very
slow
go
reduce dose
2 (3) drug
regimen
further dose
reduction
MP, CTX-P
VD, Ld
2 or 3 drug
regimen
Ludwig© 2013
Frail
Instruments for assessing fraility and allocation to
treatment groups
Assess
Age
ADL
IADL
Charlson
comorbidity
score
Fit
Unfit
Frail
Age <80 yr
Fit >80 yr
Unfit >80 yr
ADL 6
ADL 5
ADL ≤4
IADL 8
IADL 6-7
IADL ≤5
Charlson 0
Charlson 1
Charlson ≥2
Go-go
Moderate-go
Slow-go
Full-dose
Reduced-dose
Reduced-dose
regimens
regimens
Palliative
Dose level 0
Dose level -1
approach
Dose level -2
Palumbo A et al. IMW 2013
H. Ludwig 2013
Adaptation of dose according to risk factors
Agent
Dose level 0
Dose level-1
Dose level - 2
Dexamethasone
40 mg
20 mg
10 mg
Melphalan
0.25 mg/kg or 9
mg/m2
0.18 mg/kg or 7.5
mg/m2
0.13 mg/kg or 5
mg/m2
Thalidomide
100 mg
50 mg
50 mg/qod
Lenalidomide
25 mg
15 mg
10 mg
Bortezomib
1.3 mg twice
weekly, sc
1.3 mg weekly, sc
1.0 mg weekly,
sc
Prednisone
60 mg/m2
30 mg/m2
15 mg/m2
Cyclophosphamide
100 mg
50 mg
50 mg/qod
Palumbo et al.,BLOOD 2011
H. Ludwig 2013
Comorbidities relevant for treatment selection in
myeloma
Polyneuropathy
Avoid bortezomib (or use once weekly sc)
Renal impairment
Consider dose adaptations when using lenalidomide
Bone marrow insufficiency
Careful dosing of cytoreductive drugs, consider
single agent dexamethasone
Cardiac arrhythmias/
dysfunction
Cave: Thalidomide & high dose dexamethasone
Immune system
Careful dosing of cytoreductive drugs
Diabetes
Cave: high dose dexamethasone
Cognitive function/
compliance
Consider iv regimens
H. Ludwig 2013
Higher risk of mortality in patients ≥ 75 years of age
Retrospective meta-analysis of 4 EU phase III trials (N = 1,435)
with MP, MPT, VMP, and VMPT
•
Median follow up 33 months
•
Median OS in total population 50 months
•
Estimated 3-year OS 68% in patients < 75 years of age vs 57% in patients ≥
75 years of age (HR 1.44, CI 1.20-1.72, p < 0.001)
HR (95% CI)
p value
All
1.44 (1.20–0.72)
< 0.001
MP
1.21 (0.90–1.64)
0.21
MPT
1.12 (0.81–1.56)
0.49
VMP
1.62 (1.04–2.52)
0.03
VTP/VMPT
3.02 (1.86–4.90)
< 0.001
0.1
Higher mortality in patients
< 75 years of age
H. Ludwig 2013
1
10
Higher mortality in patients
≥ 75 years of age
Bringhen S, et al. Haematologica. 2013;98:980-7.
Age and Organ Damage Correlate with Poor OS:
Meta-analysis of 4 Randomized Trials
• n=1435 (≥ 65 yrs ): MPT vs MP, VMP vs MP, VMP vs VMPT-VT
Ludwig© 2013
Bringhen et al. Haematologica 2013;98(6):980-987
Phase III studies incorporating novel agents in the
non-transplant setting
New Regimen
Comparator Outcome
MPT (6 Trials)*
vs.
MP
MPT  PFS 5/6,  OS 2/6
CTDa
vs.
MP
CTDa ORR
VMP
vs.
MP
VMP  PFS,   OS
VMPT  VT
vs.
VMP
VMPT  VT
  PFS.   OS
VDT  VT or
VP
ns
VMP  VT or VP
MPR R
vs.
MPR
or MP
MPR R
  PFS
LD
vs.
Ld
Ld  PFS,   OS
LD continous
vs.
Ld x 18, vs
MPT x 12
Ld cont PFS,   OS
*Meta-analysis of the 6 trials:
H. Ludwig 2013
 PFS () OS
MPT vs MP: Meta-analysis of 1685 individual-patient
data of 6 randomized trials
OS
PFS
Median 39.3 mos
0.8
0.8
MPT
MP
1.0
HR=0.83 in favor of MPT, p=0.005*
(35.6-44.6)
Median 32.7 mos
0.4
0.4
(18.8-21.6)
(30.5-36.6)
0.2
Median 14.9 mos
0.2
MPT
MP
0.6
0.6
Median 20.3 mos
(14.0-16.6)
0.0
0.0
Survival proportion
1.0
HR=0.67 in favor of MPT, p<0.0001
0
12
24
months
36
48
0
12
24
36
48
months
*Cox model for treatment, with analysis stratified
by study using a random effects (frailty) model
Fayers et al. Blood 2011, accepted for publication 30 May 2011
H. Ludwig 2013
MPT: Pros and Cons
Pros
Cons
Survival benefit
Thalidomide toxicity
Oral regimen
Suboptimal in cytogenetic high risk
Not expensive
group
Shorter survival after relapse
H. Ludwig 2013
MP vs. VMP (VISTA) Final updated OS analysis
Median follow-up 60.1 months
•31% reduced risk of death
100
90
Median OS benefit: 13.3 months
5-year OS rates: 46.0% vs 34.4%
Patients alive (%)
80
70
60
50
40
30
Group
N
M
338
VMP
344
20
10
Event
211
176
Median
43.1
56.4
HR (95% CI)
P-value
0.695 (0.567, 0.852)
0.0004
0
0
H. Ludwig 2013
6
12
18
24
30
36
42
Time (months)
48
54
60
66
72
78
San Miguel et al. JCO 2013
Overall survival in different subgroups: VMP vs. MP
H. Ludwig 2013
San Miguel et al., JCO 2013
VMP induced CR is associated with improved
outcome
Time to progression
Treatment-free interval
Time to next therapy
Overall survival
Harousseau JL et al., BLOOD 2010
H. Ludwig 2013
VD vs. VTD vs. VMP followed by bortezomib
maintenance therapy
Parameter
VD
VTD
VMP
>VGPR
36%
44%
40%
ORR
68%
78%
71%
PNP
G3-4
15%
26%
20%
PFS
(mos)
13.8
18.4
17.3
H. Ludwig 2013
Niesvitzky R. et al., BLOO, 116 2010
Global QoL during VD, VTD and VMP
induction therapy
VD vs. VTD or VMP: shorter PFS, similar OS, better tolerance
H. Ludwig 2013
Niesvizky R et al., ASH 2011
Treatment
schedule
Treatment schedule
 511 patients (older than 65 years) randomized from 58 Italian centers
 Patients: Symptomatic multiple myeloma/end organ damage with
measurable disease
 ≥65 yrs or <65 yrs and not transplant-eligible; creatinine ≤ 2.5 mg/dL
R
A
N
D
O
M
I
Z
E
VMP
Cycles 1-9
Bortezomib 1.3 mg/m2 IV: days 1,8,15,22*
Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4
9 x 5-week cycles in both arms
VMPT
Cycles 1-9
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/day continuously
NO MAINTENANCE
Until relapse
MAINTENANCE
Bortezomib 1.3 mg/m2 IV: days 1,15
Thalidomide 50 mg/day continuously
* 66 VMP patients and 73 VMPT patients were treated with twice weekly infusions of Bortezomib
H. Ludwig 2013
PFS and OS: VMP vs VMPT –VT
Progression free survival
landmark analysis
Overall survival
Palumbo A et al. ASH 2012
H. Ludwig 2013
Overall
survival
Overall survival, Landmark analysis
Landmark analysis
Age < 75 years
1.00
ISS 1-2
1.00
0.75
0.75
0.75
0.50
0.50
0.50
0.25
0.25
0.25
HR 0.60, 95% CI, 0.41-0.89, p=0.009
HR 0.66, 95% CI, 0.43-1.00, p =.05
0.00
HR 0.45, 95% CI, 0.24-0.86, p =.01
0.00
0.00
0
10
20
30
40
50
60
70
Age ≥ 75 years
1.00
0
10
20
30
40
50
60
0
70
ISS 3
1.00
0.75
0.75
0.50
0.50
0.50
0.25
0.25
0.25
HR 0.76, 95% CI, 0.42-1.37, p =.36
10
20
VMPT
VT maint.
VMP
No maint.
H. Ludwig 2013
30
40
50
Off therapy
60
70
20
30
40
50
60
70
VGPR/PR
HR 0.80, 95% CI, 0.54-1.20, p =.28
HR 0.64, 95% CI, 0.31-1.31, p =.22
0.00
0
10
1.00
0.75
0.00
CR
1.00
0.00
0
10
20
VMPT
VT maint.
VMP
No maint.
30
40
50
Off therapy
60
70
0
10
20
VMPT
VT maint.
VMP
No maint.
30
40
50
Off therapy
60
70
Overall survival from relapse
Overall survival from relapse
1.00
3-years OS
VMPT-VT
Median OS
47%
27.8 months
46%
27.3 months
0.75
Patients (%)
VMP
0.50
0.25
HR 0.92, 95% CI, 0.66-1.28, p =.63
0.00
0
10
20
30
40
50
60
Time (months)
H. Ludwig 2013
Palumbo et al. ASH 2012 (Abstract 200)
VMPT-VT versus VMP in newly diagnosed
elderly patients
• Significant OS benefit in patients
– < 75 years of age (none in pts > 75 years)
– With stage ISS 1-2 (tendency for  OS in stage ISS 3)
– With CR (none in pts with VGPR/PR)
• Benefit in ‚good risk‘ patients with CR only
• Grade 3- 4 adverse events during VT maintenance
– PN 7%
– Hematological toxicity 5%
– Infection 3%
– Discontinuation due to AEs 12%
H. Ludwig 2013
Palumbo et al. ASH 2012 (Abstract 200), oral presentation
How to reduce toxicity of Bortezomib and and
maintain efficacy?


H. Ludwig 2013
Bortezomib once weekly

longer duration of therapy

similar cumulative dose

similar efficacy

less toxicty (G3/4 neurotoxicity)
Bortezomib subcutaneously

10 times lower serum peak concentration

similar area under the curve

less neurotoxicity

similar efficacy
-
MPR-R vs. MPR vs. MP (MM015 trial)
N = 459, 82 centers in Europe, Australia, and Israel
Open-Label
Extension Phase
Double-blind Treatment Phase
Cycles (28-day) 1-9
RANDOMIZATION
MPR-R
M: 0.18 mg/kg, days 1-4
P: 2 mg/kg, days 1-4
R: 10 mg/day po, days 1-21
Cycles 10+
Maintenance
Lenalidomide
10 mg/day
days 1-21
MPR
M: 0.18 mg/kg, days 1-4
P: 2 mg/kg, days 1-4
R: 10 mg/day po, days 1-21
Placebo
MP
M: 0.18 mg/kg, days 1-4
P: 2 mg/kg, days 1-4
PBO: days 1-21
•
•
Disease
Progression
Lenalidomide
(25 mg/day)
+/Dexamethasone
Placebo
Stratified by age (<75 years vs > 75 years) and stage (ISS I/II vs III)
ISS, International Staging System; MP,
melphalan, prednisone; MPR,melphalan, prednisone,lenalidomide
; MPR-R, melphalan, prednisone,lenalidomidewith
lenalidomidemaintenance; PBO, placebo.
H. Ludwig 2013
-
Progression-Free
andand
Overall
Survival
Progression-free
overall
survival
All Patients
Median PFS
100
4-year OS
MPR-R
31 months
MPR-R
59%
MPR
14 months
MPR
58%
MP
13 months
MP
58%
100
HR 0.898
75
HR 0.395
50
P < .001
HR 0.796
25
P = .135
0
0
10
20
Time (Months)
30
40
Patients (%)
Patients (%)
75
P = .579
50
HR 1.089
P = .648
25
0
0
10
20
30
40
Time (Months)
• TTP HR advantages were similar: MPR-R vs MP = 0.337; MPR vs MP = 0.826
HR, hazard ratio; MP,melphalan, prednisone; MPR,melphalan, prednisone,lenalidomide ; MPR -R, melphalan, prednisone,
lenalidomidewith lenalidomidemaintenance; OS, overall survival; PFS, progression
free survival; TTP, time to progression.
H. Ludwig 2013
50
60
PFS and
OS
With
R and MPR
PFS
and
OS MPR
with -MPR-R
and MPR
Patients Aged
65-75 Years
patients
aged 65-75 years
Median PFS
100
4-Year OS
MPR-R
31 months
MPR-R
69%
MPR
15 months
MPR
61%
MP
12 months
MP
58%
100
Patients (%)
75
HR 0.301
P < .001
50
HR 0.618
P = .006
Patients (%)
HR 0.706
HR 0.902
25
0
0
10
20
Time (Months)
30
40
P = .639
50
25
0
P = .133
75
0
10
20
30
40
Time (Months)
HR, hazard ratio; MP, melphalan, prednisone; MPR, melphalan, prednisone, lenalidomide; MPR-R, melphalan, prednisone,
lenalidomide
with lenalidomide maintenance; OS, overall survival; PFS, progression-free survival.
H. Ludwig 2013
50
60
FIRST: Phase 3 trial of Lenalidomide +
low-dose Dex vs MPT (IFM 07-01; MM-020)
Centres in EU, Switzerland, APAC, USA, and Canada
Inclusion
criteria
N = 1,623
• Previously
untreated MM
• Age  65 years or
not eligible
for a transplant
• No neuropathy
of grade > 2
Primary end-point: PFS
R
A
N
D
O
M
I
Z
A
T
I
O
N
Rd (28-day cycle; until disease progression)
Lenalidomide 25 mg/day, days 1–21
Dexamethasone* 40 mg/day, days 1, 8, 15, and 22
Rd (28-day cycle; up to 18 cycles)
Lenalidomide 25 mg/day, days 1–21
Dexamethasone* 40 mg/day, days 1, 8, 15, and 22
MPT (6-week cycle; up to 12 cycles )
Melphalan* 0.25 mg/kg/day, days 1–4
Prednisone 2.0 mg/kg/day, days 1–4
Thalidomide* 200 mg/day
*In patients aged > 75 years: Dex 20 mg/day,
melphalan 0.20 mg/kg/day, thalidomide 100 mg/day
H. Ludwig 2013
NCT00689936. Available from: www.clinicaltrials.gov.
What is the optimal duration of first line therapy?
Trials & duration of therapy (months)
VMP (Vista)
12
MPT trials
6-18.5
CTDa
6-9
MPR-R
9, R untill PD
VMPT-VT
12.5, VT maintenance: 2
years
LD (MM20)
Continously until
PD/intolerance
Duration of therapy: minimally 6, maximally 12 months
Most experts recommend ≈ 9 months
H. Ludwig 2013
Outcome with novel combinations
CR rate (%)
Median PFS (months)
Median OS (months)
rare
11–20
29 - 43.45 - 49.42
-
14*
32
MPT3
10
20.3
39
CTDa4
13
13
33
VMP5
30
21.7–27.4
56.4
MPR-R6
10
31
59% (4-yr OS)
VMP-VT/VP7
42
35
58% (5-yr OS)
VMPT-VT8,9
42
35.3
59.3% (5-yr OS)
≥PR 75% vs.
62%
28% ↓ risk for PD
22% ↓ risk for death
MP1,2
BP2
LD
continuous10
1MTCG.
J Clin Oncol 1998;16(12):3832-42
2Ludwig et al., BLOOD 2009
2Pönisch et al. J Cancer Res Clin Oncol. 2006;132:205-12.
3Fayers et al. Blood 2011; 118(5):1239-1247
4Morgan et al. Blood 2011;118:1231-8
H. Ludwig 2013
5San
Miguel et al. JCO 2013; 31(4): 448-455
et al. N Engl J Med 2012;366(19):1759-69
7Mateos et al. Blood 2012; 120: 2581-2588
8Palumbo et al. ASH 2012 (Abstract 200), oral presentation
9Palumbo et al. ASH 2011 (Abstract 653), oral presentation
10Facon et al. ASH 2013 (Abstract 2), oral presentation
6Palumbo
Hematologic CR correlates with long PFS
and OS in elderly patients treated with novel agents
• Retrospective analysis: 3 randomized European trials of GIMEMA and
HOVON groups (N=1175)
• First-line treatment
MP (n=332), MPT (n=332), VMP (n=257), VMPT-VT (n=254)
OS
PFS
CR
VGPR
P<0.001
PR
VGPR
Probability
Probability
CR
PR
P<0.001
Significant benefit also seen when analysis is restricted to patients
>75 years old
H. Ludwig 2013
Gay et al. Blood 2011; 117(11):3025-31
Immunophenotypc CR correlates with OS
GEM2005 >65y
100
PFS
80
60
40
Immunophenotypic CR
90% at 3y
“Stringent CR”
38% at 3y
Conventional CR
57% at 3y
PR (≥70% reduction)
28% at 3y
20
Paiva et al; J Clin Oncol. 2011;29(12):1627-33.
H. Ludwig 2013
Cytogenetic abnormalities are a major prognostic
factor in elderly patients with MM: IFM experience
1,890 patients (median age 72, range 66–94), including 1,095 patients
with updated data on treatment modalities and survival
OS according to t(4:14)
1.00
OS according to del(17p)
1.00
p < 10.6
0.75
Probability of OS
Probability of OS
p < 10.4
0.50
0.25
0.75
0.50
0.25
t(4:14) neg
t(4:14) pos
del(17p) < 60
del(17p) ≥ 60
0.00
0.00
0
1
2
3
Time (years)
4
5
0
1
2
3
Time (years)
4
5
Whatever the treatment, t(4;14) and del(17p) were associated with shorter PFS and OS;
similar results were achieved in the subgroup of 335 patients > 75 years
H. Ludwig 2013
1. Avet-Loiseau H, et al. J Clin Oncol. 2013 31(22):2806-9. 2. Hulin et al. Blood 2012:[abstract 204].
The challenge of high-risk CA [t(4;14),
del(17p), t(14;16)] in NDMM elderly patients
Study
MPT/MP1
No of pts with
high-risk CA
Outcome of high-risk CA patients
NR
NR
CTDa/MP1
(MRC Myeloma IX)
NR
CTDa does not overcome the effect of high-risk
CA and is not significantly better than MP in
high-risk CA
RD/Rd2 (E4A03)
21
2y OS=76% for high-risk CA vs 91%
VMP/MP3 (VISTA)
46
Absence of OS benefit, median OS 44.1mo.
VMP vs 50.6 mo., MP
44
Adverse prognosis of both t(4;14) and del (17p)
regardless of induction and maintenance.
Median OS t(4;14)=29 mo., del(17p) = 27mo.
VMP/VTP – VT/VP4
(GEM-05)
First generation novel agents only partly overcome the negative prognosis
of high-risk CA in newly diagnosed elderly patients with MM
H. Ludwig 2013
1. Bergsagel PL, et al. Blood. 2013;121:884-91. 2. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.
3. San Miguel J, et al. J Clin Oncol. 2013;31:448-55. 4. Mateos MV, et al. Blood. 2011;118:4547-53.
Maintenance studies - summary
Thalidomide
 PFS
no improvement in OS
 Reduced OS after relapse
Negative impact on high risk pts
Clinical practice
recommendations
50 mg for ≈ 12 mos may be considered
Lenalidomide
Bortezomib-thalidomide
H. Ludwig 2013
 PFS
-no improvement in OS
-increased risk for SPM
Tendency for  PFS and  OS but not
significant superior over VP
Summary: Treatment results in elderly patients
 MPT,  PFS, +/- OS, can be toxic in elderly pts
 VMP,  PFS  OS, may induce severe PNP
 Ld,  PFS,  OS, low dose Dex recommended
 Thal-Dex, an option for fit pts
 CTDa vs MP,  overall response rate,  CR, VGPR
 Bendamustine-Pred, approved for first line TX
 Thalidomide maintenance  PFS, but not OS
 MPR with Lenalidomide maintenance PFS, but not OS
 VT maintenance  not significantly better than VP
H. Ludwig 2013
The natural course of multiple myeloma
Maintenance
H. Ludwig 2013
Treatment of relapsed/refractory MM
General considerations
Components of initial therapy
– Alkylating-based
– Dexamethasone-based
– IMiD-based
– Bortezomib-based
Patient status and type of relapse
– Age, performance status, glucose
metabolism
– Aggressive vs non-aggressive
relapse
– Bone marrow reserve
Efficacy of initial therapy
– Quality of response
– Renal function impairment
– Pre-existing peripheral
neuropathy
– Tolerance of tretament
– Oral vs. iv therapy
– Duration of respose
IMiD, immunomodulatory derivative; MM, multiple myeloma
H. Ludwig 2013
Treatment of Relapsed/Refractory Myeloma
Frontline Therapy successful?
Yes
No
Long duration of response
Yes
Select other TX (Class switch)
No
Repeat first line TX
Select other TX
Bortezomib based frontline TX:
IMiD based frontline TX
Pomalidomide
H. Ludwig 2013
IMiD-based
TD
MPT
CTD
Rd
(MPR)
Old Type
MP
DCEP
M-100 +
ASCT
Bort-based
VD
VMP
VTD
Ludwig et al.
The Oncologist
2011
Retreatment with bortezomib:
a meta-analysis including 23 studies
• 23 trials, 1051 patients
• Patients refractory or not refractory to bortezomib
• 11 studies including bortezomib-refractory pts
• 6 studies excluding bortezomib-refractory pts
• 6 studies missing information on bortezomib-refractory pts
• Combinations
• Bortezomib ± Dex: 4 studies
• Bortezomib + combination therapy: 19 studies
H. Ludwig 2013
Knopf et al. IMW 2013 (Abstract P-228), poster presentation
Results of meta-analysis of retreatement with bortezomib
in different risk groups
ORR
TTP
(months)
OS
(months)
Relapsed
57%
8.5
19.7
Relapsed/>refractory
19%
5.9
20.4
≤ 4 prior TX lines
43%
8.2
13.3
> 4 prior TX lines
29%
7.1
20.0
Boz + Dex
51%
7.9
19.2
Combination
36%
7.1
16.2
Pooled analysis
51%
8.4
19.2
Variable
H. Ludwig 2013
Knopf et al., IMW 2013
Carfilzomib a second generation
proteasome inhibitor
H. Ludwig 2013
Single agent Carfilzomib in relapsed/refractory
patients
Progressive disease at enrollment, Relapsed from 2 prior TX lines, Must include bortezomib
Must include thalidomide or lenalidomide, Refractory to last line
Response
category
All patients
(n=267)
High risk
cytogenetics
(n=71)
CR
0.4%
0
VGPR
5.1%
4.2%
PR
18.3%
25.4%
MR
13.2%
4.2%
ORR
37%
29.5%
PFS(median)
3.7 mos
3.6 mos
DOR (median)
7.8 mos
6.9 mos
Siegel D et al., BLOOD 2012
H. Ludwig 2013
Pomalidomide + LoDex vs HiDex
(MM-003): Phase III Trial Design
Stratified by age (≤ 75 vs > 75 yrs), number of
previous treatments (2 vs > 2), disease
population (refractory vs relapsed/refractory
vs intolerant/refractory)
Patients with
relapsed/refractory
myeloma
(N = 455)
POM + LoDex
Pomalidomide 4 mg on Days 1-21 +
Dexamethasone 40 mg (if ≤ 75 yrs) or
20 mg (if > 75 yrs) on Days 1, 8, 15, 22
(n = 302)
HiDex
Dexamethasone 40 mg (if ≤ 75 yrs) or
20 mg (if > 75 yrs) on Days 1-4, 9-12, 17-20
(n = 153)
•
Primary endpoint: PFS
•
Secondary endpoints: OS, ORR, DOR, safety
San Miguel JF, et al. ASCO 2013. Abstract 8510.
H. Ludwig 2013
28-day cycles
Until PD*
Until PD*
Follow-up for OS and
SPM until 5 yrs
Post enrollment
Companion trial
MM-003C:
Pomalidomide
21/28 days
*Independently adjudicated in real time.
Thromboprophylaxis indicated for patients receiving
pomalidomide or with history of DVT.
Pomalidomide + LoDex vs HiDex: Key
Criteria for Pts With Relapsed/Refractory MM
•
All patients
– Refractory to last therapy
– ≥ 2 previous therapies
• ≥ 2 consecutive cycles of lenalidomide and bortezomib (alone or in combination) or
adequate previous alkylator therapy
– Failed bortezomib and lenalidomide
• Progression within 60 days; PR with progression within 6 mos, and/or bortezomib
intolerant after ≥ 2 cycles and achieving ≤ MR
– Refractory or relapsed/refractory
• Primary refractory (never achieved better than PD to any therapy) or relapsed and
refractory (relapsed after having ≥ SD for ≥ 2 cycles of therapy to ≥ 1 previous regimen
and then developed PD ≤ 60 days of completing their last treatment)
San Miguel JF, et al. ASCO 2013. Abstract 8510.
H. Ludwig 2013
Pomalidomide + LoDex vs HiDex
(MM-003)
PFS (ITT Population)
Mos
H. Ludwig 2013
OS (ITT Population)
Mos
San Miguel JF, et al. ASCO 2013. Abstract 8510.
Pomalidomide + LoDex vs HiDex
Adverse Events (MM-003)
AE, %
POM + LoDex
(n = 300)
HiDex
(n = 150)
 Neutropenia
48
16
 Anemia
33
37
 Thrombocytopenia
22
26
30
24
13
8
 Bone pain
7
5
 Fatigue
5
6
 Asthenia
4
6
 DVT/PE
1
0
 Peripheral neuropathy*
1
1
Discontinuation due to AEs
9
10
Grade 3/4 hematologic AEs
Grade 3/4 nonhematologic AEs
 Infections
– Pneumonia
Grade 3/4 AEs of interest
*Includes hyperesthesia, peripheral sensory neuropathy, paraesthesia, hypoesthesia, and polyneuropathy.
H. Ludwig 2013
San Miguel JF, et al. ASCO 2013. Abstract 8510.
Zoledronic Acid vs Clodronate in Newly
Diagnosed MM: SREs
•
Significantly reduced incidence of SREs* with zoledronic acid vs
clodronate
– Regardless of presence of bone lesions at baseline
Patients With an
SRE (%)
HR: 0.74 (P = .0004)
CLO
40
30
35.3%
27.0%
ZOL
20
10
0
0
18 24
30 36 42
6
12
Time From Randomization (Mos)
Patients at Risk, n
ZOL
981 663 506 390 284 201 138 97
CLO
979 629 465 337 256 173 112 74
*SREs defined as vertebral fractures, other fractures, spinal cord compression, and the requirement for
radiation or surgery to bone lesions or the appearance of new osteolytic bone lesions.
Morgan GJ, et al. ASH 2010. Abstract 311.
H. Ludwig 2013
Planned and/or ongoing studies
VD vs VTD vs VMP + V maintenance (UPFRONT study)
VRd vs Rd + Rd maintenance (SWOG S0777)
Rd vs MPT vs Rd + Rd maintenance (MM20/IM(FIRST trial)
Rd vs MPR vs CRP + maintenance R vs RP (EMNTG)
MPT+T vs MPR+R (HOVON 87-NMSG 18, ECOG EA1A06)
CTDa vs RCD +/- R maintenance (MRC Myeloma XI)
VP vs VMP vs VCP + VP maintenance (EMNTG)
Carfilzomib + MP (CARMYSAP trial): ORR of 92% (40% VGPR). EHA 2012
MLN9708 plus LD and MLN9708 plus MP: EHA 2012
Rd vs MEL140 (DSMM XIII)
Pomalidomide + Dex vs Dexamethasone: MM 005
Alternating treatment with different regimens: VMP and RD (PETHEMA/GEM)
Bortezomib + Bendamustine + Prednisone (PETHEMA/GEM)
H. Ludwig 2013
New drugs in clinical evaluation
Agent
Mechanism of action
Panobinostat, Vorinostat,
Givinostat, Romidepsin
HDAC inhibitor
Perifosine, GSK2110183
Akt inhibitor
Temsirolismus, Everolismus
mTOR inhibitor
Selumetinib
MEK/ERK inhibitor
Plitidepsin (aplidin)
Jun N-terminal Kinase (JNK) activator,
anti-angiogenic activity
Dinaciclib
CDK inhibitor
MLN8237
Aurora kinase inhibitor
ARRY-520
Kinesin spindle protein (KSP) inhibitor
Elotuzumab
anti-CS1
Daratumumab
anti-CD38
BHQ880
anti-DKK1
BT062
anti-CD138
Tabalumab
Anti-B cell activiating factor (BAFF)
BI-505
Anti-intercellular adhesion molecule 1
(ICAM-1)
H. Ludwig 2013
Recommendations for clinical practice
 Assess
- comorbidities
- degree of functional impairment
 Select most appropriate drug regimen
 Adapt dose if required
 Consider the increased risk of infections within
first weeks/months of therapy
 Optimize supportive care
-Antibiotics, antivirals, growth factors, anti-thrombotics
H. Ludwig 2013
The future looks bright for elderly
myeloma patients
Thank you for your attention
H. Ludwig 2013
H. Ludwig 2013