risk stratification in the older patient; what are our ... · risk stratification in the older...

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


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


Why treat unfit elderly patients?

Enjoying life is associated with living longer

Steptoe and Wardle, Arch of Intern Med 2012;172(3):273-5


MM precludes an enjoyable life Disease control is of importance


However, not at the cost of side effects


Possible with IMiDs and proteasome inhibitors?


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.


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.



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


Courtesy of Cyrille Hulin Hulin et al. ASH 2012 (Abstract 204), oral presentation.


Toxic side effects from first line treatment

precludes second line treatment?


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



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


Highlights the need for specific tailored strategies for very elderly patients to maximize

tolerability and optimize efficacy


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?


Unfit = ?


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.


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


Are there tools available to define unfit elderly MM patients?


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


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



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


FIT 0 UNFIT 1 FRAIL ≥ 2


Frailty score predicts outcome


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


0.00 0 12 18 24 30 36

Months 6


Overall Survival Subgroup analysis indicates the importance of frailty

compared to age and chromosomal abnormalities



Frailty score predicts non-hematological toxicity and discontinuation rate

Non-hematological toxicity Discontinuation rate


Cum

. Inc

. Non

-hae

mat

olog

ical

AE

s

0.00

0.25

0.50

0.75

1.00

0 12 18 24 Months


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


www.myelomafrailtyscorecalculator.net



How to implement this frailty score in clinical practice?

Frailty score-based treatment?

Which regimen? Which dose?


How to treat unfit elderly patients tomorrow in general clinical practice?

Which regimen?


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


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%


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


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


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.


How to treat unfit elderly patients tomorrow in general clinical practice?

Dose


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


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


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


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


Novel methods to define frailty Dutch HOVON 123 study

MPV in patients >75 years of age

FUNCTIONAL ASSESSMENTS

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