Friday, December 2, 2016San Diego, California

Treatment Advances in Multiple Myeloma: Expert Perspectives on Translating Clinical Data to Practice

This program is supported by educational grants from Amgen, Celgene Corporation, Karyopharm, Takeda Oncology, and The Binding Site.

Image: Copyright©2016 DNA Illustrations. All Rights Reserved

Program Director

Brian G.M. Durie, MDMedical Director, AMyCCo-Chair Myeloma Committee, SWOG Chairman, International Myeloma FoundationSpecialist in Multiple Myeloma and Related Disorders Cedars-Sinai Outpatient Cancer CenterLos Angeles, California

Brian G.M. Durie, MD, has disclosed that he has received consulting fees from Celgene, Johnson & Johnson, Onyx, and Takeda

Jesús F. San-Miguel, MD, PhDDirector of Clinical and Transnational MedicineClinica Universidad de NavarraUniversidad de NavarraPamplona, Spain

Jesús F. San-Miguel, MD, PhD, has disclosed that he has received consulting fees, honoraria, and fees for non-CME/CE services received directly from a commercial interest or their agents (eg, advisory board) from Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, and Novartis.

Faculty

Bruno Paiva, PhDDepartment of Hematology and ImmunologyFlow Cytometry Core - CIMA LAB DiagnosticsUniversity of NavarraPamplona, Spain

Bruno Paiva, PhD, has disclosed that he has received consulting fees from Celgene, Janssen, Merck, Novartis, and Takeda; funds for research support from Celgene and EngMab; and other honorarium for lectures from Amgen, Celgene, Janssen, and Takeda.

Faculty

ModeratorBrian G.M. Durie, MD

Faculty PresentersJesús F. San-Miguel, MD, PhD Bruno Paiva, PhD

How Should We Use Maintenance for Patients in Clinical Practice?

Image: Copyright©2016 DNA Illustrations. All Rights Reserved

Pt Case Example

65-yr-old male presents with:– 60% BM PCs

– 3.5 IgG-K M-spike (no immune paresis)

– High LDH

– ISS III

– t(4;14), no del(17p)

He enrolled in the phase III SWOG S0777 trial and was randomized to receive eight 21-day cycles of VRd

The pt is in CR at the end of induction

MRD was assessed after induction and was positive (10-5)

What would you recommend now?

A. Observation

B. Lenalidomide maintenance for up to 2 yrs

C. Lenalidomide maintenance until progression

D. Bortezomib maintenance for up to 2 yrs

E. ASCT followed by lenalidomide maintenance

F. ASCT followed by bortezomib maintenance

G. Unsure

Expert Recommendations

Expert RecommendationBrian G.M. Durie, MD ASCT followed by lenalidomide maintenanceShaji Kumar, MD ASCT followed by lenalidomide maintenancePhilippe Moreau, MD ASCT followed by lenalidomide maintenanceBruno Paiva, PhD ASCT followed by lenalidomide maintenanceS. Vincent Rajkumar, MD ASCT followed by bortezomib maintenanceJesús F. San-Miguel, MD, PhD ASCT followed by lenalidomide maintenance

Role of Maintenance Therapy in Multiple Myeloma

Jesus San-Miguel, MD, PhDUniversity of Navarra, Spain

Consolidation• Improve response/deeper

following therapy– By administration of treatment

for a limited period

Maintenance• Maintain response achieved

following therapy– By administration of treatment

for a prolonged period

What is the goal of consolidation ormaintenance therapy??

Young, transplant candidate pts

Elderly pts

Role of Maintenance Therapy in Multiple Myeloma

Maintenance is not a new concept …...in the 90‘s IFN was used following ASCTand pulses of MP to maintain the response

Maintenance Treatment With Thalidomide*

Caveats: Role in CR, duration of maintenance, toxicity, outcome after relapse

1. Spencer A et al. IMWG 2013 Kyoto2. Attal M et al. Blood. 2006;108:3289.3. Barlogie B et al. N Engl J Med. 2006;354:1021.4. Barlogie B et al. Blood. 2008;112:3115.

6 randomized trials have compared thalidomide ± pred vs nothing orpamidronate or prednisone or IFN

> PFS in all 6 trials…………….. but improved OS in only 3 Meta-analysis: modest benefit in PFS and OS (± 6 m)

5. Lokhorst HM et al. Blood. 2010;115:1113. 6. Morgan GJ, et al. Blood. 2012;119:7.7. Stewart AK et al. Blood. 2010;116: Abstract 39.

1. Sonneveld P, et al. J Clin Oncol. 2012;30:2946. 2. Rosiñol, et al. ASH 2012; Abstract 334.

Maintenance With Bortezomib-Based Therapy

Study DetailsMedian

f/uResults

≥ nCR ≥ VGPR PFS OSPAD/HDM/bortezomib[1]

vs

VAD/HDM/thalidomide

41 m

49%*

34%

76%*

56%

35 m*

28 m

Median not reached

HR: 0.77 (0.60-1.00)

P = .049

Induction/HDM/ bort + thal vs thal vs IFN x 3 yrs[2]

24 m 74% — 50.6 m**40.3 m32.5 m

78% @ 5 y72%70%

*Significant difference between arms**Median fw 58,6 m , P = .03IFN: 3 MU/sc 3 times a wk. Thal: 100 mg/day. Bort: one cycle/3 mos.

Lenalidomide vs Placebo After ASCT: PFS From Randomization

2nd Malignancies: 6,5% vs 2%

Attal, M. N Engl J Med. 2012;366:1782-1791. (Updated Feb 2015)

0.0

00.2

50.5

00.7

51.0

0

0 6 12 18 24 30 36

Placebo Revlimid

OS: 75% at 5 yrs in both arms

Len

Placebo

46 m

24 m

P < 10-8

IFM 2005-02PFS

2nd Malignancies: 8 vs 3%

McCarthy P. N Engl J Med. 2012;366:1770-1781. (Updated Nov 2014)

Len

Placebo

53 m

26 m P < 10-8

CALGB 100104

Median OS: 76 vs NR, P = .001

PFS PFS

Len

Placebo

37 m

26 m

4-yr OS: 80% vs 62%, P = .02

GIMEMA MM-RV-209

Palumbo, et al. N Engl J Med. 2014;371:895-905.(Gay ASH 2013; Abstract 2081)

Meta-Analysis of Overall Survival WithLenalidomide Maintenance: Median Follow-up of 80 m

0.00 10 20 30 40 50 60 70 80 90 100 110 120

0.2

0.4

0.6

0.8

1.0

26% reduction in risk of death, representing an estimated 2.5-yr increase in median survivala

605 578 555 509 474 431 385 282 200 95 20 1 0604 569 542 505 458 425 350 271 174 71 10 0

Overall Survival, mos

Surv

ival

Pro

babi

lity

Pts at risk

7-yr OS

62%

50%N = 1209 LENALIDOMIDE CONTROLMedian OS, mos (95% CI)

NE(NE-NE)

86.0(79.8-96.0)

HR (95% CI) 0.74 (0.62-0.89) P =. 001

a Median for lenalidomide treatment arm was extrapolated to be 116 mos based on median of the control arm and HR (median: 86 mos; HR: 0.74).

Attal M, et al. ASCO 2016. Abstract 8001. HR, hazard ratio; NE, not estimable; OS, overall survival.

LENa CONTROLa HR (95% CI)

Age 372 375 0.68 (0.54-0.86)233 229 0.83 (0.63-1.10)

Sex 322 349 0.65 (0.52-0.83)283 255 0.91 (0.69-1.19)

ISS stage 411 440 0.65 (0.52-0.81) 113 90 1.04 (0.72-1.51)

Response after ASCT66 80 0.63 (0.35-1.16)

320 339 0.70 (0.54-0.90)218 210 0.86 (0.65-1.15)

Prior induction therapy 147 146 0.48 (0.31-0.75)458 458 0.82 (0.67-1.00)

Adverse-risk cytogeneticsb 56 36 1.18 (0.66-2.10)231 243 0.79 (0.59-1.06)

CrCl after ASCTc 33 25 0.73 (0.33-1.60)379 404 0.74 (0.59-0.92)

Overall Survival: Subgroup Analysis

a Number of pts. b Cytogenetic data were available only for the IFM and GIMEMA studies. c CrCl post-ASCT data were available only for the CALGB and IFM studies.ASCT, autologous stem cell transplant; CR, complete response; CrCl, creatinine clearance; HR, hazard ratio; ISS, International Staging System; LEN, lenalidomide; OS, overall survival; PD, progressive disease; PR, partial response; SD, stable disease; VGPR, very good partial response.

Favors controlFavors LEN

Attal M, et al. ASCO 2016. Abstract 8001.

Myeloma XI: Trial Design

Non-Intensive PathwayRandomize

1:1CTD RCD

Assess Response

NC + PD CR + VGPR PR + MR

CVD

Randomise

Assess Response

Assess Response

No maintenance

High-Dose Melphalan & ASCT

ASCT, autologous stem cell transplant; CR , complete response; CTD , cyclophosphamide (500mg p.o. D1,8,15), thalidomide (100-200mg p.o. daily), dexamethasone (40mg p.o. D1-4, 12-15); CTDa, cyclophosphamide (500mg p.o. D1,8,15, 22), thalidomide (50-200mg p.o. daily), dexamethasone (20mg p.o. D1-4, 15-18); MR, minimal response; NC, no change; PD, progressive disease; PR, partial response; RCD, cyclophosphamide (500mg p.o. D1,8,15), Lenalidomide (25mg p.o. D1-21), dexamethasone (40mg p.o. D1-4, 12-15); RCDa , cyclophosphamide (500mg p.o. D1,8), Lenalidomide (25mg p.o. D1-21), dexamethasone (20mg p.o. D1-4, 15-18); VCD, Bortezomib, cyclophosphamide, dexamethasone; VGPR , very good partial response.

1. Rev (15.07.2014) Myeloma X1 Trial Protocol v5

Maintenance Randomization**

Lenalidomide 10 mg

maintenance

Lenalidomide 10 mg + Vorinostat

300 mg maintenance

Randomize 1:1

CTDa RCDa

Assess Response

NC + PD CR + VGPR PR + MR

CVD CVDNothing

Randomise

Assess Response

Assess Response

No maintenance

Maintenance Randomization

Lenalidomide 10 mg

maintenance

Lenalidomide 10 mg + Vorinostat

300 mg maintenance

**Pts entered into the RCD arm and assessed as NC or PD at the end of RCD induction are not eligible for the maintenance randomisation

Intensive Pathway

ASH2016 abstracts

CVDNothing

Jackson, et al. ASH2016. Abstract 1143.

0

10

20

30

40

50

60

70

80

Len maint. No maint.

PFS

, mos

HR 0.46; P < .0001

Post-ASCT

05

10152025303540

Len maint. No maint.P

FS, m

os

HR 0.44; P < .0001

NSCT

60

28

26

12

Myeloma XI: PFS Len Maintenance vs No Maintenance Median Follow-up: 26 mos

• Primary endpoint maintenance comparison: PFS and OS• Len maintenance doubles PFS vs no maintenance: 55% reduction in the risk of progression or death

– Median PFS 37 vs 19 mos (HR: 0.45 [95% CI: 0.39-0.52], P < .0001)• Significant improvement in PFS was observed in each pathway and across subgroups • Main grade 3/4 AEs: neutropenia (35%), thrombocytopaenia (7.4%), anaemia (4.4%), PN (1.4%) • SPMs: Hematologic incidence 0.3% vs 0.9%; slight excess in older pts, mostly noninvasive and did not

impact outcome benefit demonstrated

4 Independent Phase III Clinical Trials Investigated Lenalidomide Maintenance Post-ASCT

Coop trial PFS Hazard Ratio

IFM2005-02[1] 0.50

CALGB 100104[2] 0.48

GIMEMA RV-209[3] 0.44

Myeloma XI[4] 0.45

1. Attal M, et al. NEJM 2012;366:1782-91.2. McCarthy P, et al. NEJM 2012;366:1770-81.3. Palumbo A, et al. NEJM 2014;371:895-905.4. Jackson, et al. ASH2016. Abstract 1143.

Is there any role for maintenance therapy?

Elderly MM Patients

Thalidomide: Effect of Maintenance on PFS/OS

Study Regimen N CR (IF–) TTPPFS/EFS Overall Survival

Palumbo (Blood 2008;112:3107)

MPT (T maint.)MP (no maint.)

129126

16%4%

21.8 m14.5 m

NS: 45 m vs 47.6 mP = .79

Wijermans(JCO 2010;28:3160)

MPT (T maint.)MP (no maint.)

165168

2%2%

13 m9 m

40 m vs 31 mP = .05

Waage A(Blood 2010;116:1405)

MPT (T maint.)MP (no maint.) 363 13%

4%15 m14 m

NS: 29 m vs 32 mP = .35

• Thal-IFN vs IFN alone after induction with Thal/Dex or MP:Benefit in PFS but not in OS (Ludwig H. Haematologica 2010)

• Thal vs no maintenance after induction with CTDa or MP:Benefit in PFS (11m vs 9 m) but not in OS (Morgan G. Blood 2012)

Duration of Thal maintenance therapy short, due to toxicity.

HR 0.63, 95% CI, 0.46-0.88, p =.006

4-years OS Median OS

VMP

VMPT-VT

55% 54.2 months

67% Not reached

4-years OS Median OS

VMP

VMPT-VT

55% 54.2 months

67% Not reached

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50 60 70

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50 60 70

Pat

ient

s (%

)

Time (months)

Influence of Maintenance: VMPT + VT vs VMP

Palumbo A, et al. J Clin Oncol. 2010;28:5101-5109.

Median PFS: 37 m

VT continuous therapyVMPT

0

25

50

75

100

0 10 20 30 40 50

VMP

VMPT-VT

P < .0001

HR: 0.48

CR (IF–) after VMPT->VT increased up to 42% (maintenance)

VMP

VMPT-VT

4-y OS: 67%

VT continuous therapyVMPT

0

100

Pat

ient

s (%

)

25

50

75

0 10 20 30 40 50 60 70MonthsMonths

Pat

ient

s (%

)

Bortezomib ± Thalidomide MaintenanceModified VMP vs VTP Followed by Maintenance With VT or VP in Newly Diagnosed Elderly Pts With MM (GEM2005)

CR (IF–) increased from 24% (after induction) up to 42% (maintenance)

Mateos MV et al. Blood. 2012;120:2581.

VISTA: PFS 21m VISTA: 5-y OS: 46%; Time in months from 1st randomization

OS

Time in months from 1st randomization

PFS

6050403020100

1.0

0.8

0.6

0.4

0.2

0.0

Pro

porti

on o

f Pts

VT: 39 m

VP: 32m

P=0.1

Pro

porti

on o

f Pts

VT: Not reached5-y OS: 69%

VP: 60m

P=0.1

6050403020100

1.0

0.8

0.6

0.4

0.2

0.0

OS

Lenalidomide MaintenanceMM-015: MPR-R vs MPR vs MP

Palumbo, et al. N Engl J Med. 2012;366:1759-1769.

Median PFS

MPR-R 31 mos

MPR 14 mos

MP 13 mos

No differences were observed so far in OS

HR 0.49 P < . 001

Time (mos)0 5 10 15 20 25 30 35 40

0

25

50

75

100

HR 0.40P < . 001

FIRST Trial: Len/Dex (18 Cycles or Continuous) vs MPT

Median PFSRd (n = 535) 26 mosRd18 (n = 541) 21 mosMPT (n = 547) 21.9 mos

Hazard ratioRd vs. MPT: 0.69; P = 0.0006Rd vs. Rd18: 0.70; P = 0.0001

Rd18 vs. MPT: 1.03; P = 0.70349

Time (months)

Pts

(%)

100

80

60

40

20

00 6 12 18 24 30 36 42 48 54 60

72 w

ks

PFS

Facon T, et al. ASH 2016. Abstr 241.Hulin C, et al. J Clin Oncol. 2016;Epub ahead of print.

100

80

60

40

20

00 6 18 24 30 36 42 48 54 6012 66 72

Pts

(%)

Median OSRd (n = 535) 59 mosRd18 (n = 541) 62 mosMPT (n = 547) 49 mos

Hazard ratio Rd vs MPT: 0.78; P = 0.002Rd vs Rd18: 0.91; P = 0.305Rd18 vs MPT: 0.83; P = 0.034

OS

SPM, %Solid tumourHaematological

6.00.8

6.90.4

5.96.2

Median follow-up 67 mos, data cutoff 21 Jan 2016PFS: Rd continuous vs MPT: HR 0.69 (0.59-0.79) P < .00001 OS: Rd continuous vs MPT: HR 0.78 (0.67-0.92) P = .0023

Time (months)

VMP (x9) + Len/Dex (x9): PFS and OSGEM/Pethema GEM2010 Trial

Median follow-up: 30 months (9-43)OS

Sequential : 72% at 3 yrs

Alternating: 74% at 3 yrs

PFS

Sequential: 32m

Alternating: 34 m

p=NS

20,0010,000,00

1,0

0,2

454035302520151050

1,0

0,8

0,6

0,4

0,2

0,0

group

454035302520151050

1,0

0,8

0,6

0,4

0,2

0,0 p=NS

VISTA: 21mFIRST: 26m (cont Rd); 21 m (Rd18)

VISTA: 68% at 3 yrsFIRST: 70% (cont Rd), 66% at (Rd18) 3 yrs

Mateos, et al. Blood. 2016;127:420-425.

Lenalidomide single agent

Len vs Len+Dex: To determine which of the dual mechanisms of lenalidomide action, antitumoral and immunomodulatory, is more effective at maintaining the response.

Len + PI (Ixazomib / Carfilzomib)

Len + PI + anti-CD38 or Elo??

Len + PD-L1 inhibition

Optimal Maintenance Treatment: Number of Agents and Duration

One, two, three drugs???

Maintenance Therapy After ASCT: Future

IFM/DFCI 20091 Len x 1 yr vs len until DP

ECOG-ACRIN E1A112 Len x 2 yr vs len until DP

Myeloma XI3 Len vs len + vorinostat vs no maintenance

PETHEMA GEM 20144 Len vs len + ixazomib x 2 yrs ( MRD+ Pts cont x 3y)

SWOG7 Len vs len+ ixazomib until DP

GMMG-HD65 Len-dex vs len-dex + elotuzumab

GIMEMA6 Len vs len + carfilzomib

BMT CTN 14018 Len vs len + vaccination

AFT-409 Len vs len + durvalumab vs len + daratumumab vs len + ACY241TOURMALINE-MM310 Ixazomib for up to 2 yrs vs placebo

HOVON 131 MM-IFM 2015-0111 Daratumumab vs placebo

1. NCT01208662 at www.clinicaltrials.gov. 2. NCT01863550 at www.clinicaltrials.gov. 3. NCT01554852 at www.clinicaltrials.gov. 4. NCT02406144 at www.clinicaltrials.gov. 5. NCT02495922 at at www.clinicaltrials.gov.6. NCT02203643 at www.clinicaltrials.gov. 7. SWOG S1606 study. 8. NCT02728102 at www.clinicaltrials.gov. 9. Alliance study proposal.10. NCT02181413 at www.clinicaltrials.gov. 11. NCT02541383 at www.clinicaltrials.gov.

+/- Dara

Induction Consolidation Maintenance

(except Dara arm)

GEM 2017 for Fit, Elderly Pts: VMP/Rd vs KRd +/- Dara

D

D

DRdDR

DR

How Should We Monitor Patients During Maintenance Therapy?

Bruno Paiva, PhD

The true value of CR relies on the MRD status, and CR without MRD is no better than PR

Prog

ress

ion-

free

surv

ival

(%)

Time from response assessment (mos)

MRD– (n=316) median PFS: 58 mosCR (n=128) median PFS: 24 mosnCR (n=96) median PFS: 21 mosPR (n=199) median PFS: 26 mos< PR (38) median PFS: 9 mos

MRD– vs CR: P <.001CR vs nCR: P =.127

Ove

rall

surv

ival

(%)

Time from response assessment (mos)

MRD– (n=316) median OS: 145 mosCR (n=128) median OS: 59 mosnCR (n=96) median OS: 63 mosPR (n=199) median OS: 59 mos< PR (38) median OS: 32 mos

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

MRD-positive MRD-positive

Clinical benefit after CR vs MRD negativity among pts with high-risk cytogenetics

Overall Survival

0.0 0.2 0.4 0.6 0.8 1.0 1.2

0.0 0.2 0.4 0.6 0.8 1.0 1.2

OverallTransplant eligibleTransplant ineligibleISS IISS IIISS IIIStandard-risk FISHHigh-risk FISH

HR 95% CI P0.37 0.29-0.47 < .0010.34 0.26-0.45 < .0010.53 0.34-0.82 .0040.26 0.16-0.43 < .0010.46 0.32-0.65 < .0010.46 0.29-0.75 .0020.39 0.28-0.55 < .0010.35 0.19-0.66 .001

Reduced risk after MRD–

HR 95% CI P0.62 0.53-0.72 < .0010.65 0.55-0.78 < .0010.58 0.42-0.82 .0020.59 0.44-0.79 < .0010.72 0.57-0.91 .0050.55 0.39-0.77 < .0010.66 0.50-0.87 .0040.76 0.44-1.32 .330

Reduced risk after CR

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

OverallTransplant eligibleTransplant ineligibleISS IISS IIISS IIIStandard-risk FISHHigh-risk FISH

CR

MRD

Time from MRD assessment at cycle 9 (months)

P <.001 P =.009

Time from MRD assessment at cycle 9 (months)

Tim

e to

pro

gres

sion

(%)

Ove

rall

surv

ival

(%)

MRD– (n=25), median TTP: NRCR & MRD+ (n=22), median TTP: NR<CR & MRD+ (n=80), median TTP: 15m

50403020100

100

80

60

40

20

0

50403020100

100

80

60

40

20

0

MRD– (n=25), 3y OS: 83%CR & MRD+ (n=22), 3y OS: 53%<CR & MRD+ (n=80), 3y OS: 58%

P =.13

P =.84

Paiva B et al. Blood 2016;127(25):3165-74

Can persistent MRD after induction be controlled with further treatment?

Another 9 cycles Another 9 cycles

Median time on maintenance in the Phase III Trial SWOG S0777: 385 days

Avet-Loiseau H, et al. Blood. 2015;126: Abstract 191.

What is the meaning of persistent MRDafter maintenance therapy

10-5 – 10-6

P value (trend) < .0001

[10-6; 10-5]

[10-5; 10-4]

≥ 10-4

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pts

With

out P

rogr

essi

on (%

)

0 6 12 18 24 30 36 42 48

Mos Since Randomization

MRD at postmaintenance

<10-6

MRD+ pts have different outcomes according to their cytogenetic profile

Standard-risk FISH / MRD– (n=40); median TTP: NR

High-risk FISH / MRD– (n=7); median TTP: NR

Standard-risk FISH / MRD+ (n=66); median TTP: 15 mos

High-risk FISH / MRD+ (n=19); median TTP: 12 mos

50403020100

100

80

60

40

20

0

Tim

e to

Pro

gres

sion

(%)

P <.001

Time From MRD Assessment (Mos)

P =.70

P =.02

Paiva B, et al. Blood. 2016;127:3165-3174.

Walker B, et al. J Clin Oncol. 2015;33:3911-3920.

ZFHX4

IRF4

EGFR1

Clinical impact of mutations in selected genes: Myeloma XI trial

Prognostic value of immune reconstitution in patients with persistent MRD

Time from MRD assessment (mos)

Tim

e-to

pro

gres

sion

(%)

P =.001

median TTP: NR

median TTP: 16m

PCA3

PCA1

normal PCs

median TTP: NR

clonal PCs

B-p

recu

rsor

sE

ryth

robl

asts

MRD+ with high normal PC recovery and favorable

immune profile

MRD–MRD+

Paiva B, et al. Blood. 2016;127:3165-3174As presented at ASH 2015.

Individual patient’ immune signatures

Single 8-color combination (CD45, CD138, CD38, CD56, CD27, CD19, CD117, CD81):Enumeration of 15 different BM cell populations

Patients with favorable immune profileare characterized by an increased compartment of mature B-cells

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

stratification toward precision medicine

Next-generation prognostication for precision medicine in multiple myeloma

PCA2

PCA150403020100

100

80

60

40

20

0Tim

e-to

pro

gres

sion

(%)

Time from MRD assessment (mos)

NK cells

B-cells

T-cells Prediction of outcomes based on big datasets

AgeECOGISSLDH…

Genetic landscape

Immune profiling

MRD monitoring

Prior treatment

Unsustained CR

Sustained CR

MRD positive

Which maintenance strategies are effective in patients with persistent MRD?

Maintenance?

80

100

60

20

40

0 P = .01

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

0 5 10 15 20 25 30

Next-generation MRD-negative patients:favorable outcome, but need to check for PB contamination

Flores-Montero J, et al. manuscript under review.NGF, next-generation flow.

Cell Population % Normal BMCells (Range) Case 1 Case 2

Mast cells 0.006% (0.002-0.03) 0.002% 0.0006%

Erythroblasts 6.4% (2-11.5) 8.01% 5.1%

CD19– nPC 0.05% (0.003-0.2) 0.004% 0.004%

CD19–/CD19+ nPC ratio 0.6% (0.08-1.1) 0.3% 0.08%

CD27+ B-cell precursors 0.08% (0.004-0.4) 0.0001% 0.003%

CD27– B-cell precursors 0.4% (0.05-2.2) 0.001% 0.01%

CD27+/CD27– B-cell precursor ratio 0.2% (0.04-1) 0.09% 0.3%

Mature B-cells 1.6% (0.6-3.5) 0.2% 0.1%

B-cell precursor/mature B-cell ratio 0.2% (0.03-1.1) 0.02% 0.1%

Myeloid precursors 1.8% (0.2-3.6) 0.3% 0.3%

Prog

ress

ion-

Free

Sur

viva

l (%

)

Time From MRD Assessment (Mos)

NGF– (n=37), 75% PFS: NR

InductionMRD–

HDT/ASCTMRD–

Diagnosis CRMRD+ 0.06%

ConsolidationMRD+ 0.003%

Myeloma is a patchy disease: need for continuous monitoring

Treatment stages

P = .02

PFS for patients withnegative PET-CT and negative MRD by flow

(47.7% of pts) vs otherspremaintenance

89.6%

54.5%

Moreau P, et al. Blood. 2015;126: abstract 395.

Kumar SK, et al (IMWG). Lancet Oncol. 2016;17:e328-e346.

IMWG Criteria for MRD in Multiple MyelomaIM

WG

MR

D N

egat

ivity

Crit

eria

(Req

uire

s C

R)

Sustained MRD-negative

MRD negative in the marrow (NGF or NGS) and by imaging as defined below, confirmed one yr apart. Subsequent evaluations can be used to further specify the duration of negativity (eg, MRD negative at 5 yrs, etc)

Imaging MRD-negative MRD negative as defined below (NGF or NGS) PLUS Disappearance of every area of increased tracer uptake found at baseline or a preceding PET/CT

Flow MRD-negative Absence of phenotypically aberrant clonal plasma cells by next-generation flow cytometry4 on bone marrow aspirates using the EuroFlow standard operation procedure for MRD detection in MM (or validated equivalent method) with a minimum sensitivity of 1 in 105 nucleated cells or higher

Sequencing MRD-negative

Absence of clonal plasma cells by next generation sequencing on bone marrow aspirates in which presence of a clone is defined as less than 2 identical sequencing reads obtained after DNA sequencing of bone marrow aspirates using the Lymphosight® platform (or validated equivalent method) with a minimum sensitivity of 1 in 105 nucleated cells or higher

myeloma.org/videos/ASH-Satellite-Symposium-2016

clinicaloptions.com/oncology

clinicaloptions.com/MyelomaTool

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