Maintenance therapy after autologous transplantation

Transcription

1 Maintenance therapy after autologous transplantation Sonja Zweegman MD PhD Department of Hematology Amsterdam The Netherlands

2 Disclosures Research funding from Celgene, Takeda and Janssen Participation advisory boards Celgene, Takeda, Janssen, Amgen, Sanofi

3 Second disclosure

4 Is there a rational for maintenance treatment in MM? What is the goal? Can this goal be reached? If so, with what drug? At any price?

5 PFS OS

6 MAINTENANCE SUPERIOR R R IT IS NOT THE FIRST PFS THAT IS IMPORTANT R BUT WHAT COMES NO DIFFERENCE THEREAFTER R R OVERALL SURVIVAL R R NO MAINTENANCE SUPERIOR R R

7 Is there a rational for maintenance treatment in MM? What is the goal? Can an improvement in OS be reached with maintenance? If so, with which drugs? At any price?

8 Clinical studies with data on maintenance Bortezomib V Lenalidomide R

9 Bortezomib maintenance No studies with a second randomisation bortezomib vs no bortezomib Different induction regimens 1,2 Both arms bortezomib maintenance, compared with historical control 3 N Maintenance agent Median PFS (months) 5 year OS (%) GIMEMA HOVON/GMMG Bort 1.3 mg/m 2 q 2 weeks + Thal 50 mg/d vs no maintenance Bort 1.3 mg/m 2 q 2 weeks vs Thal 50 mg/d 35 vs 25* 61 vs 51* 35 vs 28* 61 vs 55* PETHEMA Bort 1.3 mg/m 2 q 3 months + Thal 50 mg/d vs Bort 1.3 mg/m 2 q 3 months + Pred 50 mg/d 39 vs vs Palumbo A, et al. Blood. 2012;120:[abstract 200]. Updated data presented at ASH Sonneveld et al. J Clin Oncol 2012: 30; Mateos et al. Blood 2012: 120; months with VMP without maintenance

10 Does bortezomib maintenance results in superior OS? Because of induction or maintenance? Landmark analysis 12 months from randomisation [Post-Tx] R Vincristin Adriamycin Dexa Bortezomib Adriamycin Dexa HDM followed by ausct Thalidomide maintenance OS superior in the bortezomib arm (p=0.05), but Bortezomib maintenance

11 Landmark analysis

12 Bortezomib/thalidomide maintenance improves PFS but not OS The PETHEMA/GEM study randomisation after VBMCP/VBAD/B between VT/T/IFN2α and ausct Rosinol L, et al. Leukemia 2017 ;31:

13 Bortezomib maintenance following ausct NO STANDARD OF CARE

14 You might consider in renal failure HOVON65/GMMG-HD4 study borteozomib induction and maintenance overcame negative impact of creatinine level 2 mg/dl After induction 81 vs 63% renal recovery (p=0.23) OS Scheid C, et al. Leukemia 2014

15 You might consider in del17p HOVON65/GMMG-HD4 study borteozomib induction and maintenance partly overcame the negative impact of del17p Neben K, et al. Blood 2012

16 Lenalidomide maintenance 4 large phase III RCTs versus no maintenance N Maintenance agent PFS (%) OS (%) CALGB Len 10 mg 3-year PFS; 57.3 vs 28.9* 3-year 88 vs 80* Improves PFS Heterogeneous effect OS IFM Len 10 mg 4-year PFS; 43 vs 22* 4-year 73 vs 75 GIMEMA MPR vs MEL Len 10 mg Median PFS; 37 vs 26* 5-year 75 vs 58 MRC XI Len 10 mg Median PFS; 56.9 vs 30.1* 3-year 87.5 vs 80.2* 1. McCarthy PL, et al. N Engl J Med. 2012;366: and Holstein MA, et al. Lancet Haematol Sep;4(9):e431-e Attal M, et al. N Engl J Med. 2012;366: Boccadoro M, et al. J Clin Oncol. 2013;31:[suppl; abstr 8509]. 4. Jackson G, et al ASH

17 Meta-analysis for OS McCarthy P et al. JCO 2017

18 Meta-analysis for OS including MRC XI Jackson G, et al ASH

19 Lenalidomide maintenance following ausct STANDARD OF CARE

20 However, a meta-analysis

21 Are there reasons For omitting lenalidomide in specific situations?

22 Meta-analysis for OS Not in ISS III and in elevated LDH, cytogenetic high risk and renal failure McCarthy P et al. JCO 2017

23 However, in the MRC IX study superior OS also in ISS III and high risk

24 Are there reasons For omitting lenalidomide in specific situations? NO or from a patient perspective there is?

25 Meta-analysis for OS Effect only after 4 years and at 7 years 40% without success In 45% it appeared not to be necessary McCarthy P et al. JCO 2017

26 Which side effects patients take into account when deciding on maintenance therapy? PNP 27% Pancytopenia and risk on infections 24% Thrombosis 20% Fatigue 15% Nausea 8% Diarrhea and constipation 7% Burnette, et al. Cancer 2013: 119;

27 Toxicity (%) during maintenance therapy Low incidence grade III/IV but long term minimal side effects do matter BORTEZOMIB LENALIDOMIDE PNP grade 3-4 ~5 ~1 PNP ~10 ~2-23 NEUTROPENIA ~0/~2 ~60/~35-50 INFECTIONS ~24/~75 ~5/~75 THROMBOSIS ~2 ~2 FATIGUE ~1/~20 ~3/~40 GI SYMPTOMS ~5/~50 ~4/~40 Disontinuation due to toxicity ~10 ~20

28 How long your life should be extended to accept side effects of treatment? 32% wants maintenance in case life expectancy increases with only 3 months without side effects, decreases to 15% in case of moderate toxicity 35% ONLY CONSIDERS MAINTENANCE IN CASE OS BENEFIT IS >5 YEARS 32% 23% 15% Prolongation of life 1 = 3 months 2 = 6 months 3 = 1 year 4 = 2 years 5 = 3 years 6 = >5 years 7 = never SIDE EFFECTS NO MILD MODERATE Burnette, et al. Cancer 2013: 119;

29 Maintenance therapy? Yes with lenalidomide in all patients Consider bortezomib in del17p or renal failure But not forget to ask your patient!