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

jmikhael@myeloma.org