Myeloma Perspectives 2017 · Myeloma Perspectives 2017 DR. BRIAN DURIE ... High Risk SMM (Median TTP ~2 years) ... BP, CTD. Frontline Therapy Options 2017

Myeloma Perspectives 2017

DR. BRIAN DURIE DR. MARIA-VICTORIA MATEOS

Brian GM DurieJanuary 12th, 2017

International Myeloma Foundation

Key Topics

Who should be treated?

Frontline options 2017

Role of autotransplant

MRD - / MRD: Testing and management

Current relapse options?

New agents/ combos?

2


When Should Treatment Be Started?

Potential New Myeloma or Smoldering Myeloma

Observation

Any Myeloma Defining Events?• CRAB,

• >60% PC,

• FLC > 100,

• MRI > 1 focal

No Myeloma Defining Events (SMM)

Treat as Myeloma

High Risk SMM(Median TTP ~2 years)

Low Risk SMM(~5% per year PD)

Consider Treating as Myeloma

Evolving, or many high risk factors

Clinical Trials

Rajkumar SV, Landgren O, Mateos MV. Blood 2015;125:3069-75.

3


How should HR SMM be treated?

4

Gently RdDaraElo Rd

For Cure Cesar: KRd + ASCT ASCENT: KRd + dara + ASCTiStopMM: Dara + Rd


Eligibility for ASCT

Second options: VCD, VD, VTDBP, CTD

Frontline Therapy Options 2017

Induction: 3 drug regimens

YES

Maintenance

USVRdRd

VCD

Non-USVTDVCDPAD

NO

5

USRd

VRd Lite

Non-USVMPMPT

LenalidomideBortezomib


Eight 21-day Cycles of VRd

Bortezomib 1.3/mg2 IVDays 1, 4, 8, and 11Lenalidomide 25 mg/day PODays 1-14Dexamethasone 20 mg/day PODays 1, 2, 4, 5, 8, 9, 11, 12

Six 28-day Cycles of Rd

Lenalidomide 25 mg/day PODays 1-21Dexamethasone 40 mg/day PODays 1, 8, 15, 22

RandomizationN = 525

Stratification:• ISS (I, II, III)• Intent to

transplant @ progression (yes/no)

SWOG S0777 Study Design

6

Lancet Dec 2016


SWOG S0777 Outcome Measures

OutcomeMeasures VRd RdORR, % 82% 72%≥ VGPR, % 16% 8%Median PFS, mo 46 mo 30 moMedian OS, mo 75 mo 64 mo

7

Lancet Dec 2016


SWOG S0777 Progression Free Survival by Treatment Arm

8Lancet Dec 2016

VRd


Progression Free Survival (PFS) If VGPR Achieved

9

VGPR


SWOG S0777Overall Survival By Treatment Arm

10Lancet (in press) 2016

VRd


Rajkumar SV. 2016/2017

Initial Treatment of Myeloma

Not Transplant Candidate

VRd

Newly Diagnosed MM

Transplant Candidate

VRd x 4 cycles*

• Auto SCT;**• Maintenance***

(Len for std risk;

Bortez for high risk)

VRd x4 cycles

Maintenance

Delayed Transplant

Rd (if frail, age ≥75)

* Consider KRd for high risk patients** Consider tandem ASCT for intermediate and high risk***

msmart.org

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Role of Autotransplant (ASCT/HDT) Progression Free Surivival

P < 0 .0 01

0

10

20

30

40

50

60

70

80

90

10 0

Pa

tie

nts

(%

)

3 5 0 296 2 28 12 8 24no H D T35 0 309 2 61 15 3 27H D T

N a t risk

0 12 24 36 48

M o n th s o f f o l lo w -u p

H D T

no H D T

Attal M. ASH 2015 12

IFM 2009 Trial


P N S

0

10

20

30

40

50

60

70

80

90

10 0P

ati

en

ts (

%)

3 5 0 33 8 3 20 24 4 56no H D T35 0 32 8 3 09 22 6 55H D T

N a t risk

0 12 24 36 48

M o n th s o f f o l lo w -u p

H D T

no H D T

Overall Survival (OS)

Attal M. ASH 201513

IFM 2009 Trial


Role of Transplant

ASH Late Breaking Abstract #LBA-1 BMT CTN 0702

staMINA Trial PI: Ed Stadtmauer 758 patients Stratified:

• Cytogenetic risk

• B2M• Center

PFS OS PDACM 57% 86% 42%TAM 56% 82% 42%AM 52% 83% 47%

At 38 months

ACM

TAM

AM

TANDEM ASCTLEN

Maintenance

SINGLE ASCT + 4 cycles VRd

SINGLE ASCT

No differences in PFS/ OS/ PD

14


Prog

ress

ion-

free

sur

viva

l (%

)

Time from response assessment (months)

MRD- (n=316) median PFS: 58 monthsCR (n=128) median PFS: 24 monthsnCR (n=96) median PFS: 21 monthsPR (n=199) median PFS: 26 months<PR (38) median PFS: 9 months

MRD- vs CR: P <.001CR vs nCR: P =.127

Ove

rall

surv

ival

(%)

Time from response assessment (months)

MRD- (n=316) median OS: 145 monthsCR (n=128) median OS: 59 monthsnCR (n=96) median OS: 63 monthsPR (n=199) median OS: 59 months<PR (38) median OS: 32 months

MRD- vs CR: P <.001CR vs nCR: P =.657

P <.001 P <.001

GEM2000, GEM2005MENOS65, GEM2005MAS65, GEM2010MAS65 (n=777)Lahuerta JJ, et al. manuscript under review

The true value of CR relies on the MRD status

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MRD Negative

MRD Negative

PFS OS


Need for integrated next-generation immunophenotypic and sequencingtechniques for new concepts in risk

stratification towards precision medicine

16


Unsustained CR

Sustained CR

MRD-positive

Maintenance?

Which maintenance strategies are effective in patients with persistent MRD?

17

CR

MRD Negative


15 cell populations

clonal PCs

normal PCsB-cell precursors

Memory B-cells

Naïve B-cells

T-&NK-cells

Cytotoxic T-&NK-cells

CD117+ Myeloid precursors

CD117+ Erythroidprecursors

Mast cellsMonocytes

Basophils

Whole BM cellularity

Eosinophils

Neutrophils

Nucleated red cells

NEXT GENERATION FLOW-MRD monitoring in MM- immediate and simultaneous sample QC -

7.5% of samples not suited for MRD in multicenter (international) trials

18


NEXT GENERATION FLOW-MRD IN MM Next Generation Flow (NGF) vs Next Generation Sequencing (NGS)

19

NGF and NGS Testing in 31 patients (≥ VGPR)

P < 0.001

P < 0.5

NGF NGSApplicability 31/31

(100%)*27/31 (87%)*

Positive 19/27 (70%)*

13/27 (48%)*

more sensitive


NEXT GENERATION FLOW Impact of MRD on Progression-Free Survival (n=79)

80

100

60

20

40

0

Prog

ress

ion-

free

surv

ival

(%)

Time from MRD assessment (months)

P=.01

NGF- (n=37), 75% PFS: NR*

NGF+ (n=42),75% PFS: 10 months

0 5 10 15 20 25 30

Patients in VGPR, CR/sCR NGF status

20

Patients with adequate marrow sample


Induction Consolidation Maintenance

GEM 2017: New protocol to evaluate MRD

(except Dara arm)

DR

DR

21

VMP/ Rd

KRd +/- Dara


How should MRD testing be used?

Y• To assess MRD –• To study and further treat MRD +

W• Is it too soon?

or• Can be used with careful patient

education?

22

In clinical trials: throughout the disease

In clinical practice


POLLUX and CASTOR lead the way!

23

Dara combinations

Game Changer?


Early Relapse: Lenalidomide-based StudiesPOLLUX

DRd vs Rd

PFS HR (95% CI)

0.37 (0.27-0.52)

ORR 93%

≥VGPR 76%

≥CR 43%

Duration of response, mo NE

OS HR (95% CI)

0.64(0.40-1.01)

ASPIREKRd vs Rd1

ELOQUENT-2ERd vs Rd2,3

TOURMALINE-MM1NRd vs Rd4

0.69 (0.57-0.83)

0.73 (0.60-0.89)

0.74 (0.59-0.94)

87% 79% 78%

70% 33% 48%

32% 4% 14%

28.6 20.7 20.5

0.79(0.63-0.99)

0.77 (0.61-0.97) NE

1. Stewart AK, et al. N Engl J Med. 2015;372(2):142-152.2. Lonial S, et al. N Engl J Med. 2015;373(7):621-631.3. Dimopoulos MA, et al. Blood. 2015;126(23):Abstract 28. 4. Moreau P, et al. N Engl J Med. 2016;374(17):1621-1634.

Dimopoulos M, et al. EHA 2013. Abstract LB2238.

24


Early Relapse: PI-Based Studies

1. Dimopoulos MA, et al. Lancet Oncol. 2016;17(1):27-38.2. San-Miguel JF, et al. Lancet Oncol. 2014;15(11):1195-1206.3. San-Miguel JF, et al. Blood. 2015;126(23):Abstract 3026.4. Jakubowiak A, et al. Blood. 2016. Epub ahead of print.

Palumbo et al. Presented at ASCO 2016 (Abstract LBA4), oral presentation

DaratumumabDVd vs Vd

PFS HR (95% CI) 0.39 (0.28-0.53)

PFS Median mo NE

>VGPR 59%

>CR 19%

Duration of response, mo NE

OS HR (95% CI) 0.77 (0.47, 1.26)

CarfilzomibKd vs Vd1

PanobinostatPVd vs Vd2,3

ElotuzumabEVd vs Vd4

0.53 (0.44-0.65)

0.63 (0.52-0.76)

0.72 (0.59-0.88)

18.7 12.0 9.7

54% 28% 36%

13% 11% 4%

21.3 13.1 11.4

0.79 (0.58-1.08)

0.94 (0.78-1.14)

0.61 (0.32-1.15)

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Daratumumab-Revlimid-Dex(DRd)

Not refractory to Lenalidomide* Refractory to Lenalidomide

*Relapse occurring while off all therapy, or while on small doses of single-agent lenalidomide, or on bortezomibmaintenance

*Consider salvage auto transplant in eligible patients

Treatment of First Relapse*

Daratumumab-Velcade-Dex (DVd), orCyBorD

Derived from: msmart.org; Rajkumar SV, Kyle RA. Progress in Myeloma: A Monoclonal Breakthrough. N Engl J Med 2016;375:1390-1392

msmart.org

26


CyBorDDRd, DVd

First Relapse Options

Ixazomib-RdElotuzumab-Rd

Other Dara-based regimensPanobinostat-Bortez-Dex

Additional Options

Derived from: msmart.org

Second or higher relapse

27


Burden on Healthcare System and Patients

Ixazomib-Rd Carfilzomib-Rd Elotuzumab-Rd Dara-Rd Route of administration

PO IV IV IV

Hospital/clinic visit

Every 4 weeks Twice a week Weekly x 8 then twice monthly Weekly x 8, twice monthly x 4,

then Monthly

Minimum clinic visits based on 18 cycles

18 96 44 28

Administration time in clinic/ hospital per visit

0 hours Over 2 hours(130 minutes)

About 5 hours(290 minutes)

1 day6 hours

Prehydration N Additional IV hydration needed

N N

ASH 2016 Friday Satellite Symposium

28


How do you prioritize choices at first relapse?

• Efficacy• Toxicity• Ease of administration• Costs/ Reimbursement• To achieve MAXIMUM RESPONSE

29


New Myeloma Therapy combination with AIDS drug

St. Gallen, Switzerland team 34 patients; resistant to Velcade® Nelfinavir (NFV) ; oral; overcomes Velcade® resistance Combo = NFV + Velcade/ Dex; well tolerated Relapse/ Refractory patients ORR (PR or better) = 65%

ASH Abstract #487: AIDS Drug

30


New Myeloma Therapy combination with AIDS drug

ASH Abstract #487

Figure 1. Maximum relative change in serum-M protein or serum free light chain concentration in individual evaluable patients

PR VGPR

31


Venetoclax: BCL-2 Inhibitor Therapy

Shaji Kumar; AbbVie Inc. (Genentech) study 66 patients; relapse/ refractory disease Acceptable safety profile

ASH Abstract #488: BCL-2 Inhibitor

t(11;14)

40%

32


Venetoclax + bortezomib/ dex in Relapse/ Refractory Myeloma

Philippe Moreau; AbbVie Inc. (Genentech) study 66 patients; relapse/ refractory disease

ASH Abstract #975: BCL-2 Inhibitor Combo

33


Selinexor/ Dex in Relapse/ Refractory Myeloma

Dan Vogl: Karyopharm 79 patients: 48 – quad (4) refractory: Rev/ Pom/ Velcade/ Kyprolis 31 – penta (5) refractory: + dara “unmet need group”

ORR (≥ partial response) = 21% (quad); 20% (penta) Median DOR = 5 months

OS = 9.3 months Main toxicities: platelets ; GI ; fatigue

ASH Abstract #491: Anti-oncogene “export” inhibitor

“STORM” Trial

34


Selinexor/ Velcade/ Dex Combo

Bahlis; Karyopharm 22 patients; PI refractory; well tolerated

ASH Abstract #977

Table 1: Best Response by Prior Proteasome Inhibitor (PI) Treatment Status

7 (58%)

“STOMP” Trial

Also, Abstract #330: Selinexor/ Pom/ dexAbstract #973: Selinexor/ Car/ dex

35


Anti-CD19 CAR-T Cell Therapy

U Penn Team 10 patients treated; post-ASCT; safe

ASH Abstract #974

3long

VGPRs

36


What are the most exciting new/evolving therapies?

• NFV combo• Venetoclax• Selinexor• CAR-T: CD19/ BCMA• Checkpoint inhibitors• Virotherapy• Other

37


OPEN DISCUSSION

FINAL THOUGHTS

What are the most exciting new/evolving therapies?

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Thank you to our sponsors!

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Documents

Myeloma Perspectives 2017 · Myeloma Perspectives 2017 DR. BRIAN DURIE ... High Risk SMM (Median TTP ~2 years) ... BP, CTD. Frontline Therapy Options 2017