Transcript Slide 1

Treatment of Transplant
Ineligible/Elderly MM Patients
Myelomacenter.org
[email protected]
Ruben Niesvizky
Department of Medicine, Division of Hematology/Oncology,
Weill-Cornell Medical College / New York Presbyterian
Hospital, New York, NY, USA
Disclosures
• Speaker’s bureau: Celgene, Millennium, Onyx
Case
• 65 year-old Hispanic male
– Presents to emergency room with chest pain, fatigue;
found with:
•
•
•
•
•
•
•
•
Creatinine: 5.0
Hemoglobin: 8.9
Multiple lytic lesions
Total urine protein: 20 gm/24 hr
UPEP: 19.4 gms kappa light chain
SPEP: 0.1 monoclonal peak
β2M: 15.0
BM: 50% plasma cells
Case Discussion
As you discuss with him his disease and his prognosis, he
is concerned that his age precludes him from
aggressive therapy. You advise him:
1. He is a “young person with lots of experience,” and
his age should not preclude him from receiving
aggressive therapy with the intent of changing the
natural history of his disease
2. Patients over the age of 65 should not be considered
for aggressive therapies
.
The Elderly Patient
The median age at diagnosis is 70 years
• Nearly half of multiple myeloma
patients are considered elderly
• Current distinction of elderly based
on transplant eligibility (European
and North
American trials)
Elderly
28%
Older
Patients under 65 years
of age, 35%
Older patients from 65 to 75 years
of age, 28%
Elderly patients over 75, 37%
37%
35%
Palumbo A, et al. Hematology Am Soc Hematol Educ Program. 2009:566-577.; Ferlay J, et al. GLOBOCAN 2002 Cancer Incidence, Mortality and
Prevalence Worldwide. IARC CancerBase No. 5 Version 2.0. Lyon: IARC Press; 2004.; Ries LAG, et al. National Cancer Institute. SEER Cancer
Statistics Review. Source: SEER 13. Accessed August 24, 2010 at: http://seer.cancer.gov/faststats
Myeloma: 5-year Relative Survival Rates
42.9%
< 65 years
25.2 %
>65 years
SEER 1995-2001
Novel Agent Limitations in the Aging Population
Median OS<65 60 m
Median OS>65 32 m
Kumar et al. Blood 2007
Treatment of Elderly MM Patients
Leading Questions

What is the goal of treatment (does CR matter)?

What is the best induction treatment?

Is it possible to individualize the treatment?

Can novel drugs improve outcome
Treatment of Elderly MM Patients
Leading Questions




What is the goal of treatment (does CR matter)?
CR in Non-Transplant Setting
van de Velde et al. Haematologica 2007
Mean = 3.6%
Keldsen 1993
Hulin 2007
Facon 2006
Facon 2007
MEAN
Palumbo 2006
Osterborg 1993
Oken 1999
San Miguel 2007
Zervas 2001
Hernandez 2004
Waage 2007
Ludwig 2007
Joshua 1997
-20
-15
-10
-5
0
5
10
15
20
25
30
35
40
Percent Improvement in Survival
Median not available, OS calculated from 2yr (San Miguel),
3yr (Palumbo) and 5yr (Zervas) estimates
• Medline/OVID search from 1980 – Mar 2008
• 13 studies (4396 patients) meeting the criteria: randomized comparative trials in newly
diagnoses MM reporting CR or CR/nCR and survival (either median survival or survival
rate)
• Percent improvement in survival for each percent increase in the CR/nCR rate was
calculated for each study
ΔCR/nCR
OS
ΔOS
+10%
35m
+12.6m
+10%
50m
+18m
• 5 of 13 studies failed
to show association:
primarily due to the
confounding effect
of a therapy that
generates high CR
and is
simultaneously too
toxic
• Two polarizing
impact of a therapy
on survival (higher
CR leading to longer
survival vs higher
toxicity leading to
shorter survival)
confounds analysis
Hematologic CR Correlates with Long-term 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
PR
P<0.001
VGPR
Probability
Probability
CR
PR
P<0.001
•Significant benefit also seen when analysis is restricted to patients >75 years
old
Gay et al. Blood 2011; 117(11):3025-31
The Better the Quality of the Response the Longer the
Survival (Immunophenotypic CR): GEM2005>65y
PFS
100
80
Immunophenotypic CR
90% at 3y
“Stringent CR”
38% at 3y
Conventional CR
57% at 3y
PR (≥70% reduction)
28% at 3y
60
40
20
0
P =0.001
0
10
20
30
Months
40
50
60
Paiva et al; J Clin Oncol. 2011;29(12):1627-33.
Sequential Approach
NDMM Patients
Induction
PAD
Transplant
MEL100
Consolidation
Len-Pdn
Maintenance
Len
four 21-day courses
two courses
four 28-day courses
until progression
Median follow-up 66 months
PFS
Median age 70 years
OS according response
PFS according response
1.00
1.00
1.00
CR
CR
0.75
0.75
0.75
0.50
0.50
Median 47 mo
PR
0.25
0.25
VGPR
VGPR
0.50
PR
0.25
P<0.001
0.00
0.00
0.00
0
10
20
30
40
months
50
60
70
80
10
20
30
40
50
60
months
12
20
40
60
80
100
months
Gay F, et al. Gr. Emat. Milan 19 November 2012
PAD, bortezomib-pegylated doxorubicin-dexamethasone; MEL100, Melphalan100 mg/m 2; Len-Pdn, lenalidomide-prednisone; Len, lenalidomide; PFS, progression-free survival;
OS, overall survival; CR, complete response; VGPR, very good partial response; PR, partial response; NDMM, newly diagnosed multiple myeloma
CR Should Be an Important Objective in
Elderly MM Patients
Important Aim of Treatment:
Achievement of high-quality, sustained CR
balanced with acceptable toxicity
Treatment of Elderly MM Patients
Leading Questions




What is the best induction treatment?
THALIDOMIDE
MPT vs. MP : Efficacy in Newly
Diagnosed Elderly Myeloma Patients
 3 trials (IFM991, IFM012, HOVON3)………. > RR, PFS & OS
 2 trial (GIMEMA4, TURKISH5)………………. > RR, PFS
 1 trial (Nordic6 )…………………………….. > RR
RR :
CR :
PFS :
OS :
59%
10%
20,4
39,3
vs.
vs.
vs.
vs.
37 %
2,5%
15 m
32,7 m
(>22%)
(>8 %)
( 6 m)………… HR 0,67
(>6 m)…………HR 0,83
• Thal maintenance in Italian, Nordic, Hovon
1.Facon et al. Lancet 2007;370:1209–1218; 2. Hulin et al. JCO 2009; 27(22):3664-70 ; 3. Wijermans JCO 2010; 28: 3160-6; 4. Palumbo et al. Blood 2008; 112:
3107–3114; 5. Beksac M et al. Eur J Haematol 2010; 86:16-22; 6. Waage et al Blood 2010;116(9):1405-12; Fayers PM et al. Blood 2011; 118(5): 1239-47
MPT vs. MP : Toxicity
MPT
MP
32%
29%
40%**
18%
-Infection
13%**
9%
-Peripheral Neuropathy
15%**
3%
-Deep Venous Thrombosis
6%**
2%
-Toxicity-related discontinuations
35%**
5%
 Grade 3-4 hematologic Aes
 Grade 3-4 non-hematologic Aes
*Appropriate thromboprophylaxis is required
** p of significant value
Palumbo A. Haematologica 2012; Epub ahead on August 8
Other Thalidomide-based Combinations in
Front-line
Study
Results
Reference
CTDa
MP
Phase 3
≥ PR
CTDa
vs MP
64%
33%
CR
13%
3%
OS
33m
31m
Thal/Dex
*
MP
≥ PR
73%
42%
TTP
21m
29m
OS
41m
49m
Phase 3
Thal/dex
vs MP
•
•
•
Thal: 200 mg daily; Dex: 40 mg days 1-4; 9-12
Morgan et al. Blood
2011; 118(5): 12318
Ludwig et al.
Blood,2009 ;113:343543
In patients > 75 years, OS longer with MP (41 vs 20m)
In patients <75 years, similar OS
Higher mortality during 1st y with thal/dex vs MP (28 vs 16, p=0.02)
LENALIDOMIDE
Lenalidomide(R) +/- MP: MPR-R vs. MPR vs. MP
Phase III Study Scheme N=459 patients > 65years
Cycles (28-day) 1-9
MPR-R
RANDOMISATION
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+
Lenalidomide
Continued Tx
10 mg/day,
days 1-21
Primary
Comparison
MPR
MPR-R
vs. MP
M: 0.18 mg/kg,
days 1-4
P: 2 mg/kg, days 1-4
R: 10 mg/day po, days 1-21
Secondary
MP Comparison
MPR-R
MPR
M: 0.18 vs.
mg/kg,
days 1-4
P: 2 mg/kg,
Addition
of days
MPR1-4
arm per
PBO: days
1-21
EMEA
advice
Placebo
Disease
progression
Lenalidomide
(25 mg/day)
+/dexamethason
e
Placebo
Double-Blind Treatment Phase
Stratified by age (≤ 75 vs. > 75 years) and stage (ISS
1,2 vs. 3)
Open-Label Extension/
Follow-Up Phase
M, melphalan; P, prednisone; R, lenalidomide; PBO, placebo.
Response & PFS: MPR-R vs. MP vs. MPR
%RR (%CR): 77(10)
vs.
50(3)
vs. 68(3)
Median PFS
100
75
MPR-R
31 months
MPR
14 months
MP
13 months
50
HR 0.49
P < .0000001
25
HR 0.40
P = .153
0
0
5
10
15
20
25
Time (months)
Median follow-up 30 months
30
35
40
Palumbo et al. N Engl J Med 2012; 366: 1759-69
OS: MPR-R vs. MPR vs. MP
Median follow-up 30 months
Palumbo et al. N Engl J Med 2012; 366: 1759-69
AEs During Induction: MPR-R vs. MP vs. MPR
MPR-R
(N = 150)
Hematological, %
G3
MPR
(N = 152)
MP
(N = 153)
G4
G3
G4
G3
G4
Neutropenia
67
35
64
32
29
8
Thrombocytopenia
35
11
38
14
12
4
Non-hematological, %
Infections
9
1
13
2
7
-
DVT
1
-
4
-
1
-
SPM, n
12
9
4
- AML
5
2
-
- MDS
2
3
1
- Non-hematologic SPM
5
4
3
DVT, deep vein thrombosis; SMP: Second primary malignancy; AML, acute myelogenous leukemia; MDS,
myelodysplastic syndrome
Palumbo et al. N Engl J Med 2012; 366: 1759-69
BORTEZOMIB
VISTA: Bortezomib (V) as Initial Standard Therapy in Multiple
Myeloma: Assessment with Melphalan and Prednisone
• Patients: Symptomatic multiple myeloma/end organ damage with measurable
disease
– ≥ 65 years or < 65 years and not transplant-eligible; KPS ≥ 60%
R
A
N
D
O
M
I
Z
E
VMP
Cycles 1–4
Bortezomib 1.3 mg/m2 IV, d 1,4,8,11,22,25,29,32
Melphalan 9 mg/m2 IV, and prednisone 60 mg/m2 IV,
d 1–4
Cycles 5–9
Bortezomib 1.3 mg/m2 IV, d 1,8,22,29
Melphalan 9 mg/m2 IV and prednisone 60 mg/m2 IV,
d 1–4
9 x 6-week cycles (54 weeks) in both arms
MP
Cycles 1–9
Melphalan 9 mg/m2 IV and prednisone 60 mg/m2 IV,
d 1–4
• Stratification: β2-microglobulin, albumin, region
Primary
end point: TTP
Secondary end points:
CR rate, ORR, time to
response, DOR, time to
next therapy, OS, PFS,
QoL (PRO)
Bortezomib+MP (VMP) vs. MP: Efficacy Data
(682 patients)
ORR: VMP 71%, MP 35%,
CR: VMP 30%, MP 4%
Time to progression
Overall survival
52% reduced risk of progression on VMP
~36% reduced risk of death on VMP
100
VMP
MP
80
60
40
20
VMP: 24.0 months
MP: 16.6 months, P<0.000001
0
0
3
6
9
12
15
18
Time (months)
21
24
VMP
MP
80
Patients without event (%)
Patients without event (%)
100
27
60
40
Median follow-up 36.7 months
3-year OS:
VMP: 69%
MP: 54%, P=0.0008
20
0
0
4
8
12
16
20
24
28
32
36
Time (months)
San Miguel et al. N Engl J Med 2008;359:906–917; Updated by Mateos et al JCO 2010
40
OS (ITT)
31% reduced risk of death with VMP
Median OS benefit: 13.3 months
100
90
5-year OS rates: 46.0% vs 34.4%
Patients alive (%)
80
70
60
50
40
30
Group
20
10
N
Event
Median
HR (95% CI)
P-value
MP
338
211
VMP
344
176
43.1
56.4
0.695 (0.567, 0.852)
0.0004
36
42
48
Time (months)
54
60
66
72
112
158
61
78
24
34
3
1
0
0
6
12
18
Number of patients at risk:
338 301 262 240
344 300 288 270
24
30
216
246
196
232
168
216
153
199
133
176
78
San Miguel et al. ASH 2011; abstract 476
Grade 3/4 Adverse Events
VMP (n=340)
Gr 3
Gr 4
MP (n=337)
Gr 3
Gr
4
Neutropenia, %
30
10
23
15
Thrombocytopenia, %
20
17
16
14
GI, %
19
1
5
<1
Peripheral Sensory Neuropathy, %
13
<1
0
0
Pneumonia, %
5
2
4
1
Herpes Zoster, %
3
0
2
0
Hematological SPM*, n(%)
3(1%)
3(1%)
Non-hematological SPM*, n(%)
16(5%)
10(3%)
San Miguel et al. ASH 2011; abstract 476
1Howlader N, et al. SEER Cancer Statistics Review, 1975-2008.
http://seer.cancer.gov/csr/1975_2008/browse_csr.php?section=2&page=sect_02_table.07.html
Progress in the Treatment of Elderly
Patients with MM
•Novel agents SHOULD be included:
•Evidence based: bortezomib, lenalidomide > thalidomide
•Generating promising data: lenalidomide, bortezomib,
carfilzomib
Treatment of Elderly MM Patients
Leading Questions




Is it possible to individualize the treatment?
2-Year Mortality Rate for Persons Age 70
Years and Older
•
•
8% if fully independent
14% if dependent in IADL
•
•
27% if dependent in ADL
40% if institutionalized
Reuben. Am J Med. 1992;93:663.
Comorbidity is a Key Factor in Survival
Age-Comorbidity
Score
N
Actual 10-Year
Survival (%)
0-1
369
97-99
2
136
87
3
109
79
4
42
47
5
29
34
Charlson et al. J Chronic Dis. 1987;40:373.
Functional Assessment
UPFRONT Protocol
Induction: 21-day cycles
Cycles 1–4
VcD
RANDOMIZE 1:1:1
Vc: 1.3 mg/m2, days 1,4,8,11
D: 20 mg, days 1,2,4,5,8,9,11,12
VcTD
Vc: 1.3 mg/m2, days 1,4,8,11
T: 100 mg, days 1–21
D: 20 mg, days 1,2,4,5,8,9,11,12
Cycles 5–8
Maintenance:
35-day cycles
Cycles 9–13
Vc: 1.3 mg/m2, days 1,4,8,11
D: 20 mg, days 1,2,4,5
Vc: 1.3 mg/m2, days 1,4,8,11
T: 100 mg, days 1–21
D: 20 mg, days 1,2,4,5
Vc: 1.6 mg/m2,
days 1,8,15,22
Rest period:
days 23–35
VcMP
Vc: 1.3 mg/m2, days 1,4,8,11
M: 9 mg/m2, days 1,2,3,4 of every other cycle
P: 60 mg/m2, days 1,2,3,4 of every other cycle
POSTER presentation ASH: 2013
Patient Demographics and
Baseline Disease Characteristics
VcD
(N=100)
73.5 (39–91)
VcTD
(N=100)
73.0 (38–88)
VcMP
(N=100)
72.0 (42–86)
≥75 years, %
48
40
34
≥80 years, %
20
17
13
58
45
57
White
78
73
72
Black
9
19
17
Other
11
8
10
Not reported
2
0
1
IgG / IgA / Light chain, %
59 / 28 / 13
58 / 28 / 14
63 / 21 / 14
KPS 50–60 / 70–80 / 90–100, %
9 / 42 / 48
9 / 38 / 53
13 / 47 / 40
ISS stage I / II / III, %
15 / 55 / 29
36 / 33 / 31
26 / 43 / 31
Charlson co-morbidity index 0 / 1 / ≥2, %
51 / 25 / 24
55 / 30 / 15
62 / 24 / 14
Serum creatinine >1.5 x ULN, %
16
13
13
Median b2-microglobulin, mg/L
4.5
3.4
3.7
Median age, years (range)
Male, %
Race, %
Proportion of patients
PFS
(ITT population N=502)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
VcD (N=167, 40% PFS events)
VcTD (N=168, 29% PFS events)
VcMP (N=167, 36% PFS events)
Patients
remaining, n
0
VD: 168
VTD: 167
VMP:167
2
4
6
8
10
12
144
134
145
123
117
125
95
84
102
79
71
81
68
59
69
50
45
57
14 16 18 20
Time (Months)
34
32
39
25
23
32
20
17
21
17
13
16
22
24
26
28
30
15
12
11
9
6
6
7
4
3
2
–
1
–
2
–
32 34
–
–
–
–
–
–
 Median follow up was 13.4 months for the entire study population
 Median PFS was 13.8, 18.4, and 17.3 months for the VcD, VcTD and VcMP arms, respectively
 None of the pair-wise comparisons are statistically significant
Patient-reported QoL
(mean global health status score by treatment arm)
Induction
Maintenance
58
56
54
52
50
48
Score
46
44
42
40
Baseline
VD
VTD
Cycle 3
Day 1
VMP
Cycle 5
Day 1
Cycle 7
Day 1
Cycle 9
Day 1
Cycle 11
Day 1
Cycle 13
Day 1
Timepoint
 In all three treatment arms, there was a trend for decreasing QoL during induction,
followed by an improvement/stabilization in QoL during maintenance
 There was a trend for poorer QoL in the VTD vs. VD and VMP arms
UPFRONT QoL poster (Niesvizky et al., ASH 2011, abstract 1864)
Once-weekly Administration of Bortezomib as a
Strategy to Improve Tolerability
Study details
Grade ¾
GI toxicity
Grade 3/4
peripheral
neuropathy
Discontinuation
due to AE
20%
14%
34%
-
5%
17%
7%
7%
12%†
VISTA: VMP1-3
Bortezomib
twice-weekly
(GIMEMA)4
Bortezomib
once-weekly
(PETHEMA/GEM)5
Bortezomib
once-weekly
1. San Miguel et al. NEJM 2008;359:906
2. San Miguel et al. NEJM 2008;359:906; Supplementary Appendix
3. Mateos et al. J Clin Oncol 2010;28:2259-66
†Discontinuations
4. Palumbo et al. JCO 2010; 28:5101-09
5. Mateos et al. Lancet Oncol 2010;11:934-41
due to SAEs
Once-weekly Administration of Bortezomib as a
Strategy to Maintain/Improve the Ffficacy
Study details
CR+PR
CR
PFS
3 yrs-OS
71%
30%
TTP:24 m
68%
Modified VISTA4 (GIMEMA)
Bortezomib once-weekly
VMPTVT
VMP
90%
81%
42%
24%
37 m
27 m
85%
80%
Modified VISTA5 (PETHEMA)
Bortezomib once-weekly
VMP vs VTPVT vs VP
80%
23%42%
31 m
70%
VISTA: VMP1-3
Bortezomib twice-weekly
1. San Miguel et al. NEJM 2008;359:906
2. San Miguel et al. NEJM 2008;359:906; Supplementary Appendix
3. Mateos et al. J Clin Oncol 2010;28:2259-66
4. Palumbo et al. J Clin Oncol 2010;28:5101-9
5. Mateos et al. Lancet Oncol 2010;11:934-41
Once-weekly Administration of Bortezomib as a
Strategy to Improve Tolerability
Planned bortezomib
dose
Delivered bortezomib
dose
VISTA: VMP1
Bortezomib twice-weekly
67.6 mg/m2
38.5 mg/m2
Modified VISTA2
Bortezomib once-weekly
(GIMEMA)
46.8 mg/m2
39.4 mg/m2
Modified VISTA3
Bortezomib once-weekly
(PETHEMA/GEM)
36.4 mg/m2
32.9 mg/m2
Study details
Mateos et al. IMW 2011: abstract 175
Bortezomib IV versus SC
222 relapsed and/or refractory MM patients. Bz is given at conventional dose and scheme
Bortezomib IV (n=73)
Bortezomib SC (n=145)
Primary endpoint: response after 4/8cycles (single agent bortezomib or
+/-dex))
ORR
42%/52%
42%/52%
CR
8%/12%
6%/10%
TTP
9·4 m
10·4 m
Bortezomib IV
Periph Neurop
Bortezomib SC
All grades
Grade ≥3
All grades
Grade ≥3
53%
16%
38%
6%
P=0·04 and 0·03
No diferences in pharmakokinetics studies
Moreau et al. Lancet Oncology 2011; 12(5): 431-40
Arnulf B et al. Haematologica 2012: Epub ahead of print
Treatment of Elderly MM Patients
Leading Questions




Can novel drugs improve outcome
A phase 1/2 study of carfilzomib
in combination with lenalidomide
and low-dose dexamethasone
as a frontline treatment for
multiple myeloma
CR 42%
>VGPR 62%
Jakubowiak, et al Blood, 2013
ECOG
00602641
Palumbo
0109319
Fun Neo San
Celgene
0109319
SWOG
0109319
Baz 617591
OncoTx
317811
UPFRONT
507416
Evolution
507442
Boccadoro
1063179
Collaborators
Myelomacenter.org
Tomer Mark MD
Morton Coleman, MD
Roger Pearse, MD
Adriana Rossi, MD
David Jayabalan
Karen Pekle
Arthur Perry
Susan Matthew, PhD
Scott Ely, MD/MPH
Selina Chen-Kiang, PhD
Monica Guzman, PhD
Linda Tangenstam
Kathleen Pogonowski
Yasphal Agrawal, PhD
Paul Christos
Stanley Goldsmith MD
Maureen Lane PhD
Paul Christos