Personalizing Myeloma Treatment Drugs and Strategies

Transcription

1 Personalizing Myeloma Treatment Drugs and Strategies PD Dr. med. Marc S. Raab Heidelberg University Medical Center & German Cancer Research Center

2 Multiple Myeloma Clonal proliferation of malignant plasma cells. excess bone marrow plasma cells monoclonal protein osteolytic bone lesions renal disease genetically heterogeneous Punched Out Lesions Still an incurable disease 2 nd most frequent hematologic malignancy Germany: ~6000 new patients/year, 2% of all cancer deaths Raab et al., Lancet, 2009

3 Precision Myeloma Therapy Personalized by: Clinical and Patient Related Factors: Age Renal Status Previous Therapy Minimal Residual Disease Pharmacology Tumor Cell Characteristics: Cytogenetics Genomics Proteomics Immunophenotype

4 AGE Palliative way? Skating on new drugs? THE GREY ZONE Facon et al, IMW 2013

5 AGE Treatment algorithm for frail patients :EMN <Risk factors> Age over 75 years Mild, moderate or severe frailty: Patients needing help for household tasks and personal care Comorbidities: Cardiac dysfunction Pulmonary dysfunction Hepatic dysfunction Renal dysfunction Palumbo et al: Blood 2011;118:

6 Chanan-Khan et al. ClinCancRes Renal status Renal failure: 30% scr >1.5 mg/dl 20% scr >2.0 mg/dl 10% hemodialysis Degree of renal impairment related to poor outcome

7 Cumulative Percentage Cumulative Percentage Renal status GMMG-HD4/HOVON65 Trial: patients with renal failure PFS N F VAD, BLC < VAD, BLC > PAD, BLC < PAD, BLC > OS N D VAD, BLC < VAD, BLC > PAD, BLC < PAD, BLC > Mos Mos Bortezomib first choice. IMiDs feasible and effective with dose adjustments Scheid et al. Haematologica 2014;99:148-54

8 Pharmacology ARRY-520, Filanesib Kinesin Spindle Protein (KSP, eg5) is a microtubule motor protein required for mitosis and separation of spindle pole KSP inhibition prevents formation of bipolar spindle, leading to cell death Mol Cancer Ther :

9 ARRY : Prior therapies ARRY-520 ARRY dex N = 32 N = 55 Median Prior Regimens 6 8 Prior Proteasome Inhibitor 29 (91%) 55 (100%) Prior BTZ 29 (91%) 55 (100%) BTZ-refractory 17 (53%) 54 (98%) Prior IMiD 32 (100%) 55 (100%) Prior Len 31 (97%) 55 (100%) Len-refractory 24 (75%) 55 (100%) Prior Corticosteroid 32 (100%) 55 (100%) Triple-Refractory (Len, BTZ, Dex) 13 (41%) 53 (96%) Prior Alkylator 32 (100%) 55 (100%) Prior Anthracycline 16 (50%) 38 (69%) Prior Transplant 26 (81%) 49 (89%)

10 1-acid glycoprotein (AAG) is a potential selection marker for filanesib Background 1-acid glycoprotein (AAG) is an acute-phase serum protein used to diagnose and monitor inflammatory disorders AAG binds to ARRY-520 Increasing [AAG] results in increased IC 50 for ARRY-520 in vitro No correlation between [AAG] and common MM prognostic markers Hypothesis: Patients with elevated serum AAG may have sub-therapeutic exposure due to lower available ARRY-520 High pre-dose [AAG] correlates with lack of ORR and shorter time on study for patients treated with ARRY-520

11 ARRY : AAG and response ARRY-520 Single Agent All Pts 1 AAG- High AAG- Low All Pts 2 ARRY dex AAG- High AAG- Low n Median prior lines 6 8 ORR ( PR) 5 (16%) 0 (0%) 5 (24%) 8 (15%) 0 (0%) 7 (19%) CBR ( MR) 6 (19%) 0 (0%) 6 (29%) 11 (20%) 0 (0%) 10 (28%) Duration of Response (months) Time to Next Treatment (Months) OS (months)

12 2010s % recurrence 1950s Tumor Cell Characteristics N MGUS MM GK-MRI & DWI FDG-PET & PET-CT Whole genome sequencing Chr X Expression profile, acgh & GWAS Adapted from Munshi NC et al. 53rd ASH Meeting Abs 297

13 Cytogenetics Adverse prognosis: del(17p), t(4;14), +1q21 Neben et al. Blood 2012;119:

14 Cytogenetics GMMG/HOVON Trial: Subgroup Analysis N VAD/HDM/Thalidomide PFS at 36 Mos, % OS at 36 Mos, % N PAD/HDM/Bortezomib PFS at 36 Mos, % OS at 36 Mos, % All /13q t(4;14) p P <.01 in univariate analysis All data FISH, -13/13q- also karyotype if available Neben et al. Blood 2012;119:

15 Cytogenetics ABT-199, Venetoclax 1 An Increase in BCL-2 Expression Allows the Cancer Cell to Survive 2 Venetoclax Binds to and Inhibits Overexpressed BCL-2 Venetoclax 3 Apoptosis is Initiated Active Caspase Apoptosome Pro-apoptotic Proteins (BAX, BAK) Anti-apoptotic Proteins (BCL-2) BH3-only APAF-1 Cytochrome c Procaspase BAK BAX BCL-2 BCL-2 Mitochondria Mitochondria Mitochondria BH3-only family member proteins include BIM, BAD, PUMA, and NOXA

16 ABT-199: response n (%) t(11;14)-pos t(11;14)-neg CR 1 (14) 0 PR 1 (14) 0 MR 1 (14) 0 SD 2 (29) 9 (64) PD 1 (14) 2 (14) D/C 1 (14) 3 (21) ORR (CR+ PR) 29% 0% Median (range) time on study (ToS) 5.1 ( ) 1.9 ( ) Median best percent change in M-protein Decrease of 15.6% in patients with t(11;14); increase of 10.6% in non-t(11;14) Kumar et al. ASCO 2016

17 Genomics Chapman et al. Nature : ; Lohr et al. Cancer Cell (1): ; Walker et al. JCO (33): ; Walker et al. Nat. Comm : Diverse mutational landscape, 15 recurrentely mutated genes: - KRAS/NRAS: 20-25% each - FAM46C: ca. 12% - TP53: ca.8% - BRAF: 4% - TRAF3 and DIS3: <3% Mutational clusters within pathways: - MAPK pathway: ca. 50% - Akt/NF-ĸB pathways: ca.17% Limited data of clinical relevance It is the deregulation of pathways that is pathogenically important, rather than the deregulation of a specific gene.

18 Genomics BRAF V600E - PoC Screened 379 pts ~4% in myeloma Clinical relevance: OS 45 vs. 106 months Therapeutic relevance: => Clinical case Cancer Discovery 2013

19 Personalizing targeted therapy Blood 2016

20 Precision Therapy Clonal Evolution Blood 2016

21 Proteomics It is the deregulation of pathways that is pathogenetically important, rather than the deregulation of a specific gene. Morgan et al., Nat Rev Can 2012

22 AKT inhibition in Multiple Myeloma AKT inhibition with durable responses in subsets of rmm Spencer et al., Blood 2014

23 MEK inhibition in Multiple Myeloma Retrospective evaluation 58 refractory MM with RAS mutations Median of 5 prior lines 22 pts received monotherapy 4/22 achieved PR) MEK inhibition with partial responses in subsets of rmm Heuck et al., Leukemia 2015

24 RAS/RAF mutations ~ MEK/ERK activation KRAS NRAS BRAF Cases with single RAS/RAF mutation (n = 78): Overall, RAS/BRAF mut were significantly associated with activated ERK compared to RAS/BRAF wt (P = 0.042). KRAS but not NRAS is associated with ERK activation (P = 0.030), suggesting that ERK activation is depended on the individual type of mutation rather than RAS/RAF gene mutation in general.

25 Individual RAS Alleles p = KRAS G12D and BRAF V600E are consistently associated with ERK activation compared to RAS/BRAF wt (P < 0.001) KRAS G12D is more prone to ERK activation than any other KRAS mut (P = 0.007). Personalizing therapy based on cell signaling

26 TREAT EXPLORE DIAGNOSE TREAT TRANSLATE TREAT BIRMA-1 proliferation, survival BIRMA refractory MM Recruitment pool: rmm400 Pts from all DSMM / GMMG sites Centralized diagnostics at Heidelberg/Würzburg Treatment at 5 centers, Extensive translational program Investigator initiated trial BIRMA-2 proliferation, survival First signaling-driven MM trial

27 Thank you Personalized by: Clinical and Patient Related Factors: Age Renal Status Previous Therapy Minimal Residual Disease Pharmacology Tumor Cell Characteristics: Cytogenetics Genomics Proteomics Immunotype /-genomics