Risk stratification in the older patient; what are our priorities?

Transcription

1 Risk stratification in the older patient; what are our priorities? Sonja Zweegman MD PhD Amsterdam The Netherlands

2 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 Probability of survival (%) Age < 75 years Age 75 years 3-year OS < 75 years 68% 75 years 57% Time since diagnosis (years) Bringhen et al. Haematologica 2013;98(6):

3 Why treat unfit elderly patients? Enjoying life is associated with living longer Steptoe and Wardle, Arch of Intern Med 2012;172(3):273-5

4 MM precludes an enjoyable life Disease control is of importance

5 However, not at the cost of side effects

6 Possible with IMiDs and proteasome inhibitors?

7 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: , 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.

8 Even in real life - comparable PFS Analysis of IFM database, treated with MP, MPT, MPV, Len/Dex n=651 > 75 years, n= years versus >75 years versus >75 years Courtesy of Cyrille Hulin Hulin et al. ASH 2012 (Abstract 204), oral presentation.

9 Even in real life - comparable PFS Analysis of IFM database, treated with MP, MPT, MPV, Len/Dex n=651 > 75 years, n= years Toxic side effects from first line treatment precludes second line treatment? versus >75 years versus >75 years Courtesy of Cyrille Hulin Hulin et al. ASH 2012 (Abstract 204), oral presentation.

10 Negative impact of grade 3-4 nonhaematological 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):

11 Negative impact of grade 3-4 nonhaematological 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 Bringhen et al. Haematologica 2013;98(6):

12 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?

13 Unfit =?

14 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.

15 Unfit age 869 patients from 3 EMN trials, including bortezomib, lenalidomide or carfilzomib FIT 39% UNFIT 31% FRAIL 30% Median age < 75 years [%] years [%] % 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:

16 Are there tools available to define unfit elderly MM patients?

17 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:

18 Identifcation of a frailty score to predict OS Multivariate analysis adjusted for ISS, chromosome abnormatities and therapy HR (95% CI) p-value Score Age (years) ( ) > ( ) < ADL > ( ) IADL > ( ) CCI ( ) Palumbo A, et al. Blood 2015, 125:

19 Identifcation of a frailty score to predict OS HR (95% CI) p-value Score Age (years) ( ) > ( ) < ADL IADL Multivariate analysis adjusted for ISS, chromosome abnormatities and therapy FIT 0 UNFIT 1 FRAIL 2 > ( ) > ( ) CCI ( ) Palumbo A, et al. Blood 2015, 125:

20 Frailty score predicts outcome PFS OS Progression-free Survival Fit Intermediate Fitness Frail Overall Survival Fit Intermediate Fitness Frail Months Months Palumbo A, et al. Blood 2015, 125:

21 Overall Survival Subgroup analysis indicates the importance of frailty compared to age and chromosomal abnormalities Palumbo A, et al. Blood 2015, 125:

22 Frailty score predicts non-hematological toxicity and discontinuation rate Cum. Inc. Non-haematological AEs Fit Intermediate Fitness Frail Months Cumulative Incidence Discontinuation 1.00 Fit Intermediate Fitness Frail Months Non-hematological toxicity Discontinuation rate Palumbo A, et al. Blood 2015, 125:

23 Palumbo A, et al. Blood 2015, 125:

24 How to implement this frailty score in clinical practice? Frailty score-based treatment? Which regimen? Which dose?

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

26 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 Progression-Free Survival (proportion) Events, Median PFS, n n (%) months 95% CI VD (57) to 18.6 VTD (47) to 24.2 VMP (54) to Time (months) VISTA TTP 24 months 66 VISTA OS 56 months VD lowest response rate, however lowest discontinuation rate due to AE, more patients reaching maintenance, higher bortezomib dose-intensity Overall Free Survival (proportion) Events, Median OS, n n (%) months 95% CI VD (40) to NE VTD (37) to NE VMP (40) to NE Time (months) 66 Niesvizky et al. JCO 2015, June Epub ahead of print

27 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 vs. VCd vs. VMP PFS Vd VCd VMP 14 months 15 months 17 months Discontinuation Due tot toxicity Vd 12% - 4% VCd 14% - 4% VMP 20% - 4% Larocca A, et al. Leukemia 2016: 1-7

28 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

29 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 vs. CPR vs. MPR 1.00 PFS Median PFS Rd 21 months CRP 20 months MPR 24 months Larocca A, et al. Clin Lymphoma Myeloma Leuk. 2013;13(suppl1): abstract P-147 Updated data presented at IMW 2013

30 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.

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

32 Less PNP and discontinuation of therapy without losing efficacy with once weekly dosing VMP with twice-weekly bortezomib administration VISTA (N=340) GIMEMA (N=63) VMP with once-weekly bortezomib administration GIMEMA (N=190) GEM2005MAS65 (N=130) Median PFS (months) Median OS (months) NE 60.5 Grade 3-4 PN (%) Discontinuations due to AEs(%) 14.7/18.5* *14.7% discontinued VMP, and an additional 18.5% selectively discontinued bortezomib due to AEs Mateos et al. Haematologica 2014;99(6):

33 Bortezomib 1x versus 2x per week Similar treatment delivery maintenance therapy * VMP with twice-weekly bortezomib administration VMP with once-weekly bortezomib administration Planned bortezomib dose (mg/m2) VISTA (N=340) GIMEMA BIW (N=63) Delivered bortezomib dose (mg/m2) Patients completing all cycles (%) GIMEMA QW (N=190) GEM2005MAS65 (N=130) Planned bortezomib dose (mg/m2) Delivered bortezomib dose (mg/m2) Patients completing all cycles (%) * 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 Mateos et al. Haematologica 2014 Apr 24.

34 Treatment algorithm for unfit and frail MM FIT UNFIT FRAIL SCORE 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/m 2 once-weekly Dexamethasone 20 mg/week Consider LEN 15 mg Dose reduction Bortezomib 1.0 mg/m 2 once-weekly Dexamethasone 10 mg/week LEN 15 or 10 mg Palumbo A et al, Blood 25(13): , 2015 HOVON 123 trial

35 Studies needed validating prognostic value of risk score, but especially studies showing outcome of risk-based treatment Survival Probability PFS by Severity Group for All Tx Arms Severity Median PFS, mos (95% CI) Fit 28.1 ( ) Intermediate 24.5 ( ) Frail 20.0 ( ) PFS for Rd Continuous vs MPT in Frail Pts Frail Pts Rd continuous Median PFS, mos (95% CI) 20.3 ( ) MPT 20.2 ( ) Fit vs frail: HR = 0.67 (95% CI, ) Fit vs intermediate: HR = 0.83 (95% CI, ) Intermediate vs frail: HR = 0.81 (95% CI, ) PFS by Investigator, mos HR = 0.79 (95% CI, ) PFS by Investigator, mos

36 Novel methods to define frailty Dutch HOVON 123 study MPV in patients >75 years of age FUNCTIONAL ASSESSMENTS