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VU University Medical Center Amsterdam The Netherlands
Risk stratification in the older patient; what are our priorities?
Sonja Zweegman MD PhD VU University Medical Center
Amsterdam The Netherlands
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VU University Medical Center Amsterdam The Netherlands
Pro
babi
lity
of s
urvi
val
(%)
Age < 75 years Age ≥ 75 years
0.00
0.
25
0.50
0.
75
1.00
0 0.5 1 1.5 2 2.5 3 Time since diagnosis (years)
Negative impact of age on survival Meta-analysis of European trials (MP vs MPT, VMP vs VTP, VMP vs
VMPT-VT); 1435 newly diagnosed MM patients
3-year OS
< 75 years 68%
≥ 75 years 57%
Bringhen et al. Haematologica 2013;98(6):980-987
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VU University Medical Center Amsterdam The Netherlands
Why treat unfit elderly patients?
Enjoying life is associated with living longer
Steptoe and Wardle, Arch of Intern Med 2012;172(3):273-5
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VU University Medical Center Amsterdam The Netherlands
MM precludes an enjoyable life Disease control is of importance
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VU University Medical Center Amsterdam The Netherlands
However, not at the cost of side effects
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VU University Medical Center Amsterdam The Netherlands
Possible with IMiDs and proteasome inhibitors?
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VU University Medical Center Amsterdam The Netherlands
Yes, also very old patients do benefit from IMiDs and proteasome inhibitors
� Meta-analysis of MPT vs MP trials upfront ≥ 75 � Superior median OS HR 0.76
� Subanalysis of VISTA trial upfront MPV vs MP ≥ 75
� Median OS 50.7 vs 32.9 months (HR 0.70)
� Subanalysis of FIRST trial upfront Rd vs MPT > 75
� OS at 4 yrs 52% vs 39% (HR 0.72)
� Subanalysis of MM010 trial RRMM Pom-LoDex vs HiDex >70
� median OS 12.6 versus 4.9 months
Fayers PM, et al. Blood 2011:1239-47, San Miguel J. et al. J Clin Oncol. 2013:448-55, Hulin C. et al. EHA 2015, Weissel K, et al. ASH 2013 oral presentation.
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VU University Medical Center Amsterdam The Netherlands
Even in real life - comparable PFS Analysis of IFM database, treated with MP, MPT, MPV, Len/Dex
n=651 > 75 years, n=770 65-75 years
65-75 versus >75 years
Courtesy of Cyrille Hulin Hulin et al. ASH 2012 (Abstract 204), oral presentation.
65-75 versus >75 years
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VU University Medical Center Amsterdam The Netherlands
Even in real life - comparable PFS Analysis of IFM database, treated with MP, MPT, MPV, Len/Dex
n=651 > 75 years, n=770 65-75 years
65-75 versus >75 years
Courtesy of Cyrille Hulin Hulin et al. ASH 2012 (Abstract 204), oral presentation.
65-75 versus >75 years
Toxic side effects from first line treatment
precludes second line treatment?
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VU University Medical Center Amsterdam The Netherlands
Negative impact of grade 3-4 non-haematological toxicity and
discontinuation due to adverse events Meta-analysis of European trials (MP vs MPT, VMP vs VTP, VMP
vs VMPT-VT); 1435 newly diagnosed MM patients
Bringhen et al. Haematologica 2013;98(6):980-987
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VU University Medical Center Amsterdam The Netherlands
Negative impact of grade 3-4 non-haematological toxicity and
discontinuation due to adverse events Meta-analysis of European trials (MP vs MPT, VMP vs VTP, VMP
vs VMPT-VT); 1435 newly diagnosed MM patients
Bringhen et al. Haematologica 2013;98(6):980-987
Highlights the need for specific tailored strategies for very elderly patients to maximize
tolerability and optimize efficacy
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VU University Medical Center Amsterdam The Netherlands
How to optimize therapy for unfit elderly patients?
� Are there tools available to identify unfit elderly MM patients?
� Does the level of fitness affect outcome of treatment? � If so, what are the reasons for that? � How to treat unfit elderly patients tomorrow in general
clinical practice?
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VU University Medical Center Amsterdam The Netherlands
Unfit = ?
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VU University Medical Center Amsterdam The Netherlands
Unfit ≠ Performance status
� In patients with PS 0-1 � Impairments in individual geriatric assessments up
to 50% � Impairments in instrumental activity of daily living
28-44% � Frailty* in 15%
* 3 out of 5 criteria weight loss, weakness, poor endurance, slow gait speed, low physical activity
Hamaker et al. Leuk Lymph 2013.
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VU University Medical Center Amsterdam The Netherlands
Unfit ≠ age 869 patients from 3 EMN trials, including bortezomib, lenalidomide or
carfilzomib
34% of patients < 75 years is unfit/frail 4% of patients ≥ 75 years is fit
Larocca et al. ASH 2013 (Abstract 687), oral presentation Palumbo A, et al. Blood 2015, 125: 2068-74
FIT – 39% UNFIT – 31% FRAIL – 30%
Median age 71 75 80
< 75 years [%] 66 25 9
≥ 75 years [%] 4 39 57
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VU University Medical Center Amsterdam The Netherlands
Are there tools available to define unfit elderly MM patients?
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VU University Medical Center Amsterdam The Netherlands
Frailty score
� 869 patients from 3 international EMN trials � All novel agents – bortezomib, lenalidomide or
carfilzomib
� Geriatric assessments � Age � Katz’s Activity of Daily Living and Instrumental ADL � Charlson Comorbidity Index
� Multivariate analysis also including ISS and
chromosomal abnormalities
Palumbo A, et al. Blood 2015, 125: 2068-74
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VU University Medical Center Amsterdam The Netherlands
Identifcation of a frailty score to predict OS
HR (95% CI) p-value Score Age (years) ≤ 75 1 0 76-80 1.13 (0.76-1.69) 0.549 1 >80 2.40 (1.56-3.71) <0.001 2 ADL > 4 1 0 ≤ 4 1.67 (1.08-2.56) 0.020 1 IADL > 5 1 0 ≤ 5 1.43 (0.96-2.14) 0.078 1 CCI ≤ 1 1 0 ≥ 2 1.37 (0.92-2.05) 0.125 1
Multivariate analysis adjusted for ISS, chromosome abnormatities and therapy
Palumbo A, et al. Blood 2015, 125: 2068-74
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VU University Medical Center Amsterdam The Netherlands
Identifcation of a frailty score to predict OS
HR (95% CI) p-value Score Age (years) ≤ 75 1 0 76-80 1.13 (0.76-1.69) 0.549 1 >80 2.40 (1.56-3.71) <0.001 2 ADL > 4 1 0 ≤ 4 1.67 (1.08-2.56) 0.020 1 IADL > 5 1 0 ≤ 5 1.43 (0.96-2.14) 0.078 1 CCI ≤ 1 1 0 ≥ 2 1.37 (0.92-2.05) 0.125 1
Multivariate analysis adjusted for ISS, chromosome abnormatities and therapy
Palumbo A, et al. Blood 2015, 125: 2068-74
FIT 0 UNFIT 1 FRAIL ≥ 2
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VU University Medical Center Amsterdam The Netherlands
Frailty score predicts outcome
Palumbo A, et al. Blood 2015, 125: 2068-74
PFS OS
Pro
gres
sion
-free
Sur
viva
l
0.00
0.25
0.50
0.75
1.00
0 12 18 24 30 36 Months
Fit Intermediate Fitness Frail
6 O
vera
ll S
urvi
val
0.25
0.50
0.75
1.00
Fit Intermediate Fitness Frail
0.00 0 12 18 24 30 36
Months 6
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VU University Medical Center Amsterdam The Netherlands
Overall Survival Subgroup analysis indicates the importance of frailty
compared to age and chromosomal abnormalities
Palumbo A, et al. Blood 2015, 125: 2068-74
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VU University Medical Center Amsterdam The Netherlands
Frailty score predicts non-hematological toxicity and discontinuation rate
Non-hematological toxicity Discontinuation rate
Palumbo A, et al. Blood 2015, 125: 2068-74
Cum
. Inc
. Non
-hae
mat
olog
ical
AE
s
0.00
0.25
0.50
0.75
1.00
0 12 18 24 Months
Fit Intermediate Fitness Frail
6 C
umul
ativ
e In
cide
nce
Dis
cont
inua
tion
0.25
0.50
0.75
1.00 Fit Intermediate Fitness Frail
0.00 0 12 18 24
Months 6
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VU University Medical Center Amsterdam The Netherlands
www.myelomafrailtyscorecalculator.net
Palumbo A, et al. Blood 2015, 125: 2068-74
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VU University Medical Center Amsterdam The Netherlands
How to implement this frailty score in clinical practice?
Frailty score-based treatment?
Which regimen? Which dose?
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VU University Medical Center Amsterdam The Netherlands
How to treat unfit elderly patients tomorrow in general clinical practice?
Which regimen?
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VU University Medical Center Amsterdam The Netherlands
Two- or three-drug bortezomib containing regimen? n=502 elderly NDMM, 42% ≥75 and 18% ≥80 years
VD vs VTD vs VMP + 5 cycles maintenance V
Niesvizky et al. JCO 2015, June Epub ahead of print
VD lowest response rate, however lowest discontinuation rate due to AE, more patients reaching maintenance, higher bortezomib dose-intensity
Pro
gres
sion
-Fre
e S
urvi
val
(pro
porti
on)
0.0
0.4
0.6
0.8
1.0
0 36 48 60 Time (months)
VD 168 96 (57) 14.7 12.0 to 18.6 VTD 167 78 (47) 15.4 12.6 to 24.2 VMP 167 91 (54) 17.3 14.8 to 20.3
18 42 54 30 24 6 12
Events, Median PFS, n n (%) months 95% CI
66
0.2
VISTA TTP 24 months
VISTA OS 56 months
Ove
rall
Free
Sur
viva
l (pr
opor
tion)
0.0
0.4
0.6
0.8
1.0
0 36 48 60 Time (months)
VD 168 68 (40) 49.8 35.7 to NE VTD 167 62 (37) 51.5 38.5 to NE VMP 167 66 (40) 53.1 41.1 to NE
18 42 54 30 24 6 12
Events, Median OS, n n (%) months 95% CI
66
0.2
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VU University Medical Center Amsterdam The Netherlands
Two or three-drug bortezomib containing regimen?
n=152 elderly NDMM, 100% ≥75, 16% fit, 30% unfit, 54% frail Vd vs VCd vs VMP
maintenance V day 1+15 until PD
Vd VCd VMP vs. vs.
Larocca A, et al. Leukemia 2016: 1-7
PFS Vd 14 months VCd 15 months VMP 17 months
Discontinuation Due tot toxicity Vd 12% - † 4% VCd 14% - † 4% VMP 20% - † 4%
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VU University Medical Center Amsterdam The Netherlands
Frail versus fit
� At least one drug related SAE � 13% versus 0%
� Drop out during induction � 55% versus 28%
� Discontinuation due to toxicity � 26 versus 8%
� Early death � 5 of 6 patients who died within 6 months were frail
Larocca A, et al. Leukemia 2016: 1-7
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VU University Medical Center Amsterdam The Netherlands
Two or three-drug lenalidomide containing regimen?
n=662 elderly NDMM, 37% ≥75, ~30% unfit/25% frail Rd vs MPR-R vs CRP + R vs RP maintenance until PD
Rd CPR MPR vs. vs.
0.00
0.25
0.50
0.75
1.00
0 5 10 15 20 25 30 35 40 Larocca A, et al. Clin Lymphoma Myeloma Leuk. 2013;13(suppl1): abstract P-147
Updated data presented at IMW 2013
PFS
Median PFS Rd 21 months CRP 20 months MPR 24 months
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VU University Medical Center Amsterdam The Netherlands
OS advantage with Rd over MPT also in > 75 year old – First trial
MPT, melphalan-prednisone-thalidomide; Rd, lenalidomide plus low-dose dexamethasone; Rd18, Rd for 18 cycles. Hulin C et al. Effect of Age on Efficacy and Safety Outcomes in Patients With Newly Diagnosed Multiple Myeloma Receiving Lenalidomide and Low-Dose Dexamethasone (Rd): The FIRST Trial. EHA 2015, abstract #S429.
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VU University Medical Center Amsterdam The Netherlands
How to treat unfit elderly patients tomorrow in general clinical practice?
Dose
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VU University Medical Center Amsterdam The Netherlands
Less PNP and discontinuation of therapy without losing efficacy with once weekly dosing
VMP with twice-weekly bortezomib administration
VMP with once-weekly bortezomib administration
VISTA (N=340)
GIMEMA (N=63)
GIMEMA (N=190)
GEM2005MAS65 (N=130)
Median PFS (months) 21.7 25.2 22.2 38.1 Median OS (months) 56.4 65.4 NE 60.5 Grade 3-4 PN (%) 13 14 2 7 Discontinuations due to AEs(%) 14.7/18.5* 22.2 13.2 12
*14.7% discontinued VMP, and an additional 18.5% selectively discontinued bortezomib due to AEs
Mateos et al. Haematologica 2014;99(6):1114-22
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VU University Medical Center Amsterdam The Netherlands
Bortezomib 1x versus 2x per week Similar treatment delivery “maintenance therapy”*
Mateos et al. Haematologica 2014 Apr 24.
VMP with twice-weekly bortezomib administration
VMP with once-weekly bortezomib administration
01020304050607080
Plannedbortezomib dose
(mg/m2)
Deliveredbortezomib dose
(mg/m2)
Patientscompleting all
cycles (%)
VISTA (N=340)GIMEMA BIW (N=63)
01020304050607080
Plannedbortezomib dose
(mg/m2)
Deliveredbortezomib dose
(mg/m2)
Patientscompleting all
cycles (%)
GIMEMA QW (N=190)GEM2005MAS65 (N=130)
* In GEM2005 bortezomib cycle day 1,4,8,11 every 3 months for 3 years * In GIMEMA bortezomib administration every 2 weeks for 2 years
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VU University Medical Center Amsterdam The Netherlands
Treatment algorithm for unfit and frail MM
Palumbo A et al, Blood 25(13):2068-74, 2015 HOVON 123 trial
FIT UNFIT FRAIL
SCORE 0 1 ≥ 2
TREATMENT
Consider AuSCT Rd
VMP [MPT]
Rd or VMP Consider Vd
[MPT]
Rd or Vd VMP-HOVON TRIAL
[MPT] Palliative care
DOSE Full
Dose reduction Bortezomib
1.3 mg/m2once-weekly Dexamethasone
20 mg/week Consider LEN 15 mg
Dose reduction
Bortezomib 1.0 mg/m2 once-weekly
Dexamethasone 10 mg/week
LEN 15 or 10 mg
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VU University Medical Center Amsterdam The Netherlands
Studies needed validating prognostic value of risk score, but especially studies showing
outcome of risk-based treatment
Severity Median PFS, mos
(95% CI) Fit 28.1 (23.0-32.0) Intermediate 24.5 (22.1-26.7) Frail 20.0 (18.7-22.1)
0 0. 0
0. 2
0. 4
0. 6
0. 8
1 . 0
2 0 4 0 6 0 8 0
Fit vs frail: HR = 0.67 (95% CI, 0.56-0.80) Fit vs intermediate: HR = 0.83 (95% CI, 0.68-1.01) Intermediate vs frail: HR = 0.81 (95% CI, 0.70-0.94)
Sur
viva
l Pro
babi
lity
0 0. 0
0. 2
0. 4
0. 6
0. 8
1 . 0
2 0 4 0 6 0 8 0
HR = 0.79 (95% CI, 0.64-0.97)
PFS by Investigator, mos
Frail Pts Median PFS, mos
(95% CI) Rd continuous 20.3 (17.7-25.3)
MPT 20.2 (17.1-23.0)
PFS by Severity Group for All Tx Arms PFS for Rd Continuous vs MPT in Frail Pts
PFS by Investigator, mos
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VU University Medical Center Amsterdam The Netherlands
Novel methods to define frailty Dutch HOVON 123 study
MPV in patients >75 years of age
FUNCTIONAL ASSESSMENTS