Genomics 102: Clinical use for treatment individualization ... - Genomi… · Genomics 102:...
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Genomics 102: Clinical use for treatment individualization
– including double hit myeloma
Lymphoma Myeloma
NYC - October 2018
Joseph Mikhael, MD, MEd, FRCPC Chief Medical Officer, International Myeloma Foundation
Professor, Translational Genomics Research Institute (TGen) City of Hope Cancer Center
Improving Survival in MM
*Yearrangesrepresenttheyearofdiagnosis.Note:BylinkingtotheSSAMasterDeathFile,survivalwasmeasuredasBmefromdiagnosisdatetothedateofdeathobtainedfromtheSSA,BmefromdiagnosisdatetothedateofinpaBentdeath,orBmefromdiagnosisdatetoSeptember30,2015;SurvivalesBmateswerepresentedformulBplemyelomapaBentsdiagnosedandtreatedduring2006-2012(n=9,521).
Myeloma is not really “one” disease
Kumar & Rajkumar -Nature Reviews Onc 2018 https://doi.org/10.1038/ s41571-018-0018-y
Kumar & Rajkumar -Nature Reviews Onc 2018 https://doi.org/10.1038/ s41571-018-0018-y
Molecular
subtype
% of Newly
Diagnosed Cytogenetics/FISH
Characteristic genes elevated
in class Risk of Relapse
MS 17 t(4;14) FGFR3, MMSET, CCND2, IL6R Moderate
MF 6 t(14;16) or t(14;20) MAF or MAFB, CCND2, IL6R High
CD-1 6 t(11;14) or t(6;14) CCND1 or CCND3 Low
CD-2 12 t(11;14) or t(6;14) CCND1 or CCND3, CD20,
VPREB3
Low
HY 31 Trisomies +3, +5, +7, +9,
+11, +15, 19
GNG11, DKK1, FRZB Moderate
LB 12 typical HY trisomies;
Frequent del13, gain of 1q,
rare gain of 11
CCND2, CST6, ARHE, IL6R Low
PR 10 Made up of all subgroups CCNB1, CCNB2, PCNA, MKI67,
TOP2A, TYMS
High
NFkB Binding Site
The Myeloma Microenvironment Is Key to Disease Pathophysiology
Bruno B et al. Lancet Oncol. 2004;5:430-442.
Increase in cytokine production and adhesion molecules
Block of programmed cell death
FAS (CD95)
Pro-caspase B FAS ligand
Collagen fibers
T Cells
NFkB–IkB complex
Protein kinases
LFA1
FADD cFLIP
Cell organelles
Fibronectin
cFLIP/FADD
NFkB
Binding Site
Natural-Killer Cells
TNFα
Monocytes
Inhibition of Anti-Myeloma Immunity
Dendritic Cells
Angiogenesis Migration Growth
BM Stromal Cells
VEGF
Myeloma Cell
SDF1 IGF1
IL-6 TNFα VLA4
VCAM1
NFkB
NFkB–IkB complex
JAK–STAT
MAPK
NFkB
AKT
SHP2
MEK
MEK/MAPK
Myeloma Cell
Interaction between genetic drivers and microenvironment changes in MM
Pawlyn C et al. Nature Reviews Cancer 2017; 17:543-556
Therapy Selection Considerations
Disease-Related • Nature of the relapse
– Biochemical vs symptomatic
• Risk stratification – High-risk
chromosomal abnormalities: del(17p), t(4;14), t(14;16)
• Disease burden
Therapy-Related • Previous therapies • Prior treatment-related
adverse event • Regimen-related toxicity • Depth and duration of
previous response • Cost to patient
Patient-Related • Renal insufficiency • Hepatic impairment • Comorbidities • Preferences • Social factors
– Support system – Accessibility to
treatment center – Insurance coverage
How can I apply genetic information to my patient now?
• High risk disease - p53del, t(4;14), t(14;16), t(14;20), chrom1 abn, plasma cell leukemia, rapid relapse post ASCT…need combination therapy, continuously with CR or MRD negativity as goal
• Specific subtypes of MM with therapeutic implications: – High Risk – usually PI +/- IMiD or MoAb – t(4:14) – treat with proteasome inhibitor based regimen – t(11;14) – responsive to venetoclax (+/- bortezomib) – p53 del – treat with proteasome inhibitor or pomalidomide – Trisomies – generally indolent course ?less aggressive Rx
Unclear where Daratumumab fits - emerging evidence for high risk disease
Carfilzomib: ASPIRE (Carfilzomib-Len-Dex vs Len-Dex) PFS by Risk Group
KRd
(n=396)
Rd
(n=396)
Risk Group by FISH N Median,
months N Median, months HR P-value (one-
sided)
High 48 23.1 52 13.9 0.70 0.083
Standard 147 29.6 170 19.5 0.66 0.004
Pomalidomide: PFS by cytogenetic risk groups for patients treated with (A) POM + LoDEX and (B) HiDEX. aLog-rank P vs. standard risk
Meletios A. Dimopoulos et al. Haematologica 2015;100:1327-1333
©2015 by Ferrata Storti Foundation
Pomalidomide: OS by cytogenetic risk groups for patients treated with (A) POM + LoDEX and (B) HiDEX. aLog-rank P vs. standard risk
Meletios A. Dimopoulos et al. Haematologica 2015;100:1327-1333
©2015 by Ferrata Storti Foundation
Daratumumab (DRD vs RD) PFS: Cytogenetic Risk
% s
urvi
ving
with
out p
rogr
essi
on
0
20
40
60
80
100
0 3 6 9 12 15 18 24
113 133 37 28
104 128 32 22
92 120 21 21
77 116 18 19
71 111 15 19
57 98 13 18
20 41 6 9
1 4 0 2
Rd std risk DRd std risk Rd high risk
DRd high risk
No. at risk Months
Rd standard risk
DRd standard risk
21
0 0 0 0
Rd high risk
DRd high risk
NR, not reached; NS, not significant. aITT/Biomarker risk–evaluable analysis set. High-risk patients had any of t(4;14), t(14;16), or del17p. Standard-risk patients had an absence of high-risk abnormalities.
§ Comparable results in 1 to 3 prior lines population
DRd n = 133
Rd n = 113
Standard risk
0.30 (0.18-0.49)
<0.0001
NR 17.1
95 82 0.0020
n = 132 n = 111
Median PFS, mo
HR (95% CI)
P value
ORR, %
P value
DRd n = 28
Rd n = 37
Median PFS, mo NR 10.2
HR (95% CI)
P value
High risk
0.44 (0.19-1.03)
0.0475
ORR, % 85 67 P value NS
n = 27 n = 36
Usmani SZ, et al. Presented at ASH 2016 (Abstract 1151), oral presentation
•
Ask The Expert: Fit Patient
33 28
6 11
22 %
• Aggressivefirstrelapse• IniBaltreatmentRVd→ASCT → lenalidomide maintenance• Relapsewithnewhigh-riskFISH• Notcurrentlyonmaintenancetherapy
N=18
How would you treat a patient who has:
Top 3 Regimen Selections: Car/Len/Dex, Dara/Len/Dex, Dara/Car/Dex
High-Risk Cytogenetics and Maintenance Therapy
– High-risk disease is associated with poor outcomes – Most respond to initial treatment, but relapse sooner – The benefit of maintenance lenalidomide monotherapy is
less clear in high-risk MM • In patients with del(17p) or t(4:14), lenalidomide
maintenance did not improve OS in the meta-analysis[b]
• Adding a proteasome inhibitor in the maintenance setting may provide a benefit for high-risk patients[c]
a. Sonneveld P, et al. Blood. 2016;127:2955-2562; b. McCarthy PL, et al. J Clin Oncol. 2017;35:3279-3289; c. Sonneveld P, et al. J Clin Oncol. 2012;113:1-14.
IMWG Consensus[a]
FISH test CD138-selected cells for: t(4;14); t(14;16); t(14;20); del(17/17p)
Suggested treatment approach for high-risk myeloma
Lonial S et al. Blood 2015;126:1536-1543
©2015 by American Society of Hematology
What about Plasma Cell Leukemia?
Lionetti M, Barbieri M, Todoerti K, et al. Oncotarget. 2015;6:26129–26141.
ROLE FOR MEKK INHIBITORS FOR UPFRONT STRATEGY?
Venetoclax
NotcurrentlyindicatedinmyelomaMayheraldthefirsttruly“targeted”therapyinMM
t(11;14)andBCL-2expressionRecallthatabout15%ofpaBentshavet(11;14)andevenmorehaveoverexpressionofBCL-2Verypromisingsingleagenttrials,thenwithproteasomeinhibitors…
Venetoclax monotherapy: Ph1 in RRMM patients
Kumar, et al. Presented at ASH 2016 (Abstract 977), oral presentation
Higher ORR (88% vs 20%) were seen in t(11;14) with a high BCL2:BCL2L1 ratio Main toxicities are thrombocytopenia (26% G3-4) and neutropenia (21% G3-4) Serious AEs: pneumoniae (8%) and sepsis (5%)
66 pts after a median of 5 prior lines of therapy: 79% refractory to last line of therapy; 61% double refractory to bortezomib and lenalidomide
30-1200 mg oral admin (MTD: 1200 mg)
0
10
20
30
40
50
Perc
enta
ge o
f Pa
tient
s
sCR CR VGPR PR
All PatientsN=66
t(11;14)n=30
ORR 21%
ORR 40%
non-t(11;14)n=36
ORR 6%
6%
8%13%
4%
10%
13%
3%3%
3%4%
0 2 4 6 8 10 12 14 16 18 20 22 240
25
50
75
100
Months since first dose
% N
ot P
rogr
esse
d
t(11;14)non-t(11;14)
No. at risk 66 33 27 20 16 9 3 1 1 1 1 1No. at risk 30 20 19 17 13 7 2 1 1 1 1 1No. at risk 36 13 8 3 3 2 1
Time to ProgressionAll Patients
0 2 4 6 8 10 12 14 16 18 20 22 240
25
50
75
100
Months since first response
t(11;14)non-t(11;14)
14 14 13 13 9 3 2 1 1 1 112 12 11 11 8 3 2 1 1 1 1 2 2 2 2 1
Duration of Overall ResponseAll Patients
Venetoclax plus bortezomib and dexamethasone
MoreauP,etal.PresentedatASH2016(Abstract975),oralpresentaBonDimopoulosMA;Haematologica2015;Epub2014Sep26.
AEs were manageable. G3-4 AEs: Thrombocytopenia (29%), anemia (15%), neutropenia (14%), diarrea (6%), PN(3%), dyspnea (6%)
Rationale for a phase 3 trial: Vd +/- Venetoclax
66 patients after >=1 prior lines of therapy (median 3). 61% refractory to the last line
.
50-1200mgoraldaily+1.3mg/m2SCTWxcycles1-8,QW9-11+20-20mg(days1,2,4,5,8,9,11,12)xcycles1-8
TTP12m
ORR:75%
≥CR:33%
Venetoclax plus bortezomib and dexamethasone
MoreauP,etal.PresentedatASH2016(Abstract975),oralpresentaBon
BCL2 Gene Expression and Clinical Response
50-1200mgoraldaily+1.3mg/m2SCTWxcycles1-8,QW9-11+20-20mgxcycles1-8
Synergy Between Carfilzomib and Venetoclax
Venetoclax and Carfilzomib
Selinexor: Novel Oral Anti-Cancer Agent Restores Tumor Suppressors & Reduces Oncoproteins
Selinexor and Low Dose Dexamethasone (Sd) in Patients with Lenalidomide, Pomalidomide, Bortezomib, Carfilzomib & anti-CD38 mAb Refractory MM: STORM Study
STORM: Selinexor + Dex (N=79)
Design: Phase II study of Sd Study Population: RRMM • 48 pts refractory to REV, POM, V, K
(Quad) • 33 pts refractory to above + anti-CD38
mAbs (Penta) Dosing & Schedule: S: 80 mg BIW for 6 or 8 doses of a 28 d cycle D: 20 mg BIW Median age: 68 yrs
Efficacy All Quad Penta
ORR CBR
21% 32%
21% 29%
20% 37%
Vogl DT, et al. ASH 2016. Abstract 491.
Safety, n (%) Gr 3/4 (≥10%) All patients
Thrombocytopenia Neutropenia
Anemia Fatigue
Hyponatremia
58 21 25 14 20
Most quad patients (83%) received 6 doses/cycle; penta patients (65%) received 8 doses/cycle
Efficacy All Responders Non-responders
mOS PFS DOR
9.3 mo 2.1 mo
NR (>11 mo)
5 mo
5.7 mo
Efficacy ORR, n (%)
Standard Risk High Risk
(17p13) t(14;16)
t(4;14)
4 (17) 6 (33) 3 (38)
1 (100) 2 (50)
Summary thus far…
High Risk – usually PI +/- IMiD or MoAb t(4:14) – treat with proteasome inhibitor based regimen t(11;14) – responsive to venetoclax (+/- bortezomib) p53 del – treat with proteasome inhibitor or pomalidomide Trisomies – generally indolent course ?less aggressive Maintenance - Most patients treated with lenalidomide
High Risk – consider PI or adding a PI t(4;14) – include a PI
Future – selinexor, CAR T, novel Abs…
Defining ‘Ultra’ High Risk MM
Usmani SZ et al. Leukemia 2015
Bi-allelic loss of TP53
Walker B et al Leukemia July 2018
Bi-allelic loss of TP53
Walker B et al Leukemia July 2018
Double Hit Myeloma
• Modeled by the Arkansas Myeloma Group • Whole-genome and exome data from 1273 patients
– Genetic factors that influenced PFS and OS • High-risk subgroup identified based on 784 pts using genomic
data, ISS and age – Bi-allelic TP53 inactivation
• OR – Amplification (>3 copies) of CKS1B (1q21) plus ISS stage 3
• Comprises 6.1% of the population • PFS 15.4 months, OS 20.7 months • Poor outcomes despite novel therapies… need more options!
Double Hit Myeloma Biallelic loss of TP53 or ISS stage III with CKS1B amplification
No bi-allelic loss of TP53 nor amp CKS1B & ISS I or ISS II and age < 65 Bi-allelic loss of TP53 or ISS III and CKS1B amp
Walker B et al Leukemia July 2018
Double Hit Myeloma Bi-allelic loss of TP53 or ISS stage III with CKS1B amplification
No bi-allelic loss of TP53 nor amp CKS1B & ISS I or ISS II and age < 65 Bi-allelic loss of TP53 or ISS III and CKS1B amp
Walker B et al Leukemia July 2018
Novel Innovations – Genomics 103??
Ongoing and Next Steps
Optimizing MRD Testing
MRD+ve patients: one size does not fit all
Goals of MRD testing: 1. Detect measurable residual tumor cells (prognostic &
surrogate biomarker) 2. Identify tumor cells able to cause imminent relapse 3. Define signatures in which MRD can be kept under control 4. Suggest subsequent treatment based on host and MRD
biology
Clonal selection
Immediate relapse?
Stable disease?
Treatment MRD+ve
What treatment?
Need treatment?
Baseline
Optimizing MRD Testing
Biologic signature of MRD chemoresistant cells
Immune monitoring to identify immune signatures that keep MRD under
control
New Opportunities with NGF Testing
*Kumar et al; Lancet Oncol (2016) sFLC: serum free light chain; NPC: normal plasma cell; CPC: clonal plasma cell
NPC NPC NPC NPC NPC
CPC CPC CPC CPC
Monitoring of Response in Blood
Tradi4onalCRProgressivedisease
• Basch E, et al. JAMA. 2017;318:197-198.
Optimizing Communication With Patients
Treat patients
as partners; communicate
openly
Improved adherence
Improved QoL
Longer survival
Thank YOU!
Joseph Mikhael, MD, MEd, FRCPC Chief Medical Officer, International Myeloma Foundation
Professor, Translational Genomics Research Institute (TGen) City of Hope Cancer Center