POST-ASH 2015 Myeloma

N Meuleman

I. J. Bordet

Myeloma: The Education Program

First line

• ASCT seems to remain the standard of care in eligible pts

• Elderly/non transplant candidate pts

Len-Dex new standard (First Study) VMP

>> MPT

J San Miguel, P Moreau, P G Richardson

How To Treat Relapsed Myeloma

Choosing becomes more and more complicated ,

especially for relapsed pts…

• Which drugs? • How much drug? • How to give them?

News From the ASH Presentations…

5

Carfilzomib, Len-Dex vs Len-Dex in

Relapsed MM: Interim Results from

ASPIRE Phase 3 Study

NonA. Keith Stewart et al

Rd

Lenalidomide 25 mg Days 1–21

Dexamethasone 40 mg Days 1, 8, 15, 22

KRd

Carfilzomib 27 mg/m2 IV (10 min)

Days 1, 2, 8, 9, 15, 16 (20 mg/m2 days 1, 2, cycle 1

only)

Lenalidomide 25 mg Days 1–21

Dexamethasone 40 mg Days 1, 8, 15, 22

Randomization

N=792

Stratification:

• β2-microglobulin

• Prior bortezomib

• Prior lenalidomide

After cycle 18, carfilzomib discontinued

28-day cycles

Primary Endpoint: Progression-Free Survival ITT Population (N=792) + Interim Overall Survival Analysis

KRD new standard of care CR/ PFS Few AE

Twice weekly

Abstract 175 Weekly Crfl

NO MTD RR compares with twice

weekly

Comparison of Sequential Vs Alternating Administration of VMP and Len-Dex in Elderly Pts with Newly Diagnosed MM

7

n = 233

MPV x 9 cycles Len-Dex x 9 cycles

MPV Rd MPV Rd MPV Rd MPV Rd MPV Rd MPV Rd MPV Rd MPV Rd MPV Rd

Sequential regimen

Alternating regimen

PFS OS

0

0 10 20 30 40 50

0,2

0,4

0,6

0,8

1,0

Sequential : 52 % 3 years

Alternating : 60 % 3 years

p = NS

Alternating : 95 % 3 years

0

0 10 20 30 40 50

0,2

0,4

0,6

0,8

1,0

Sequential: 91 % 3 years

p = NS

GEM2010MAS65 Trial, Mateos MV et al., abstr.

PFS

48

Median PFS : 22

0

25

50

75

100

0 12 24 36 Mois

MPT-T

MPT-R

HR = 0,86 (0,70-1,05) ; p = 0,14

0

25

50

75

100

0 12 24 36 48 Mois

MPT-T

MPT-R

HR = 0,79 (0,61-1,03) ; p = 0,08

OS

73

84

64

69

52

55

2 ans 3 ans 4 ans

Zweegman S et al., abstr. 179

8 HOVON87 Trial: Study Design

• MPR followed by R maintenance is equivalent to MPT followed by T maintenance for PFS and response rate

• Thalidomide is less tolerated and therefore not preferred for maintenance strategies

MPT x 9 cycles Tahl maintenance

MPR x 9 cycles Rev maintenance

Median PFS : 20

Median OS : 50

Median OS : 49

Autologous Stem Cell Transplantation

ASCT (%) CC (%) P

PFS 42 24 <0.001

OS 83 68 P=0.012

ASCT Vs. Chemotherapy Plus Lenalidomide in Newly D MM: Pooled Analysis of 2 Phase III Trials (n=529)

Len-dex

CC (VC/MP) + R X6

MEL-200 ASCT X2

• Most signicant OS advantage in good prognosis pts Karnofsky: 80-110%; ISS1; absence of del17, t(4-14), t(14-16), in pts>VGPR

# 198, F Gay et al

#197 M Cavo et al, #196 P Taccheti et al

Superior PFS2 of VTD Vs VD for newly DM, Transplant Eligible: Update Giemema MMY- 3006 (n=474)

• Giemema MMY- 3006 study: VTD • Paired with EMN02 trial: VCD (CPA 500mg/m2 J1-8)

VTD (%) VCD (%) P

ORR 93 84 P=0.003

≥VGPR 61 39 <0.001

• RR advantage confirmed in ISS2-3 and del17, t(4-14)

Superior Efficacy of VTD over VCD As Induction Therapy for Autotransplantation-Eligible, Newly Diagnosed, Myeloma Patients

VTD VD P

PFS2 76% 63% P=0.009

T2T 40 mts 31mts P=0,014

5 yrs OS 80% 73% NS Results suggest that induction and consolidation with VTD did not selected the emregence of bortezomib- R clone

• VTD vs VD induction+ consolidation • ASCT X2

And for Refractory Patients?

Dimopoulos MA, et al. abstract # 80.

Safety and Efficacy in the STRATUS Trial: Single-Arm Phase 3b Study Pomalidomide + Low-Dose Dexamethasone in Patients

With Refractory or Relapsed and Refractory MM

Confirmation of the MM03 phase III results

MM-008: A Phase 1 Trial Evaluating Pharmacokinetics and Tolerability of Pomalidomide + Low-Dose Dexamethasone in Patients With Relapsed or Refractory and Refractory Multiple

Myeloma and Renal Impairment

Matous J, et al., abstract # 4730.

MM-008 POM + LoDEX in RI: Safety

• No DLTs were observed in any patient in cohort B when dosed at 2 mg and as a result doses were escalated to 4 mg

Grade 3-4 Adverse Event, n (%) Cohort A

POM 4 mg (n= 8)

Cohort B POM 4 mg

(n= 4)

Cohort B POM 2 mg

(n= 3)

Overall (N= 15)

Neutropenia 4 (50) 1 (25) 2 (66.7) 7 (46.7)

Anemia 3 (37.5) 2 (50) 1 (33.3) 6 (40)

Infectionsb 3 (37.5) 0 2 (66.7) 5 (33.3)

Fatigue 2 (25) 0 0 2 (13.3) - Preliminary PK data support similar mean dose-normalized exposures in pts with RRMM and severe RI and those with normal renal function - No DLTs were reported for pts in cohort B - Early tolerability data are encouraging - Enrollment is ongoing in pts requiring hemodialysis

Abstract 4769, Dimopoulos et al

Three Drug Combinations Based on VD Backbone Improve Renal Function More Efficiently Than VD in Pts with Severe RI

• N=66 • eGFR< 15ml min: 64% • On dialysis: 31% • VD (33%), VDT (31%), VCD (24%), PAD (9%)

Effect of Renal and Hepatic Function on Pomalidomide Dose in Patients with Relapsed/Refractory Multiple Myeloma

Abstract 4754 , Adriana C Rossi et al

• N=120 • phase II trial of ClaPD • IR: 31% (max creat 3 mg/dl) • Hepatic dysfunction: 6%

• Baseline hepatic and renal dysfunction not predictive of dose reductions

• Ccl: Dosing should not be limited by renal (or hepatic dysfunction). Prospective studies ongoing

How to improve results of refractory MM?

… And in Belgium

Pomalidomide, Cyclophosphamide, and Dexamethasone Is Superior to Pomalidomide and Dexamethasone in Relapsed and

Refractory Myeloma: Results of a Multicenter Randomized Phase II Study

Abstract 303, Rachid Baz et al.

CBR, clinical benefit rate; Cyclo, cyclophosamide; LoDEX, low-dose dexamethasone; MR, minimal response; ORR, overall response rate; POM, pomalidomide; PR, partial response; VGPR, very good partial response.

Baz R, et al. Pomalidomide, Cyclophosphamide, and Dexamethasone Is Superior to Pomalidomide and Dexamethasone in Relapsed and Refractory Myeloma: Results of a Multicenter Randomized Phase II Study. ASH 2014, abstract #303

POM-LoDEX ± Cyclo: Response Rates

- N= 70

- LEN-refractory pts

• Median prior tt n=4

• > 70% Brt refractory

• > 1/3 CFZ refractory

Cyclo, cyclophosphamide; LoDEX, low-dose dexamethasone; PFS, progression free survival; POM, pomalidomide. .

Baz R, et al. Pomalidomide, Cyclophosphamide, and Dexamethasone Is Superior to Pomalidomide and Dexamethasone in Relapsed and Refractory Myeloma: Results of a Multicenter Randomized Phase II Study. ASH 2014, abstract #303

POM-LoDEX ± Cyclo: PFS- OS

-POM-LoDEX + Cyclo was well tolerated

- Possible increased hematologic AEs which are manageable

- The addition of cyclo for pts progressing on POM-LoDEX results in

minimal clinical benefits

Is There a Preferred Infusional Regimen for Patients with Relapsed/Refractory Multiple Myeloma?

• DCEP/ VDT-PACE/CVAD • N= 107 (52/22/33) • No statistically significant differences in outcomes

(PFS and OS) • For patients whitout bridge to transplant

chemotherapy was associated with poor outcomes, and should not be considered • Significant toxicities • Trend towards fewer adverse events in the DCEP treated

patients.

# 4757, T Griffin et al

Phase 1-2

Treatment Diseases Status

ORR ≥ VGPR

Daratumumab+ Len-Dex Rel/ RR 100%/87% 75% (TT > 6 mts)

Ixazomib+ Len-Dex + ixazomib maintenance

UnTT/ No-ASCT

90% 59% 71% (62% nCR-CR )

Oprozomib monoT (1b/2) Rel/ Rel-R 29% 14%

SAR 650984+ Len-Dex (Ib) Rel/ Rel-R 67% 37% (10mg/kg)

Elotuzumab+ Len-Dex (I/2) Rel/ Rel-R 84% 57%

#84, #83, #302, #3483, #82, #32, #33

Ulocuplimab LD/VD (I) H-IgG4 >< CXCR4

Rel/ Rel-R 55,1/40%

Monoclonal Antibodies

Next-Generation Proteasome Inhibitors

CRBN-CRL4 E3 Ubiquitin ligase

DDB1

CU

LA

4

ROC

1

LEN POM THAL

IKZF1 IKZF3 *

*Zinc fingerTranscription factors Ikaros and Aiolis /Regulator B T cell

Proteosomal dégradation

IKZF1 IKZF3

MYC IRF4

Il2 release

#4700, 2247, 3628, 639, 3432

Mecanism of resistance

CRBN: Mutation, expression level,

10 splice variant

IKZF: Mutation of CRBN binding, KFZ independence Ailos co-binding with STAT/ IRF family transcriptor factors

Serum Free Light Chains Should be the Target of Response Evaluation in Light Chain MM Rather Than

Urines: Results from the IFM2009 Trial (n=115/700)

• Backround:

– Difficulty of 24 hours urines collection

– Urine electrophoresis may not reflect the plasma response with Ur-LC very rapidly cleared

• Results- after induction :

– 79% patients had urine electrophoreses negative

– sFLC evaluation was negative in 52%

• CCL:

– sFLC assessment is much more reliable for response evaluation

– IMWG response criteria has to be reevaluate for LCMM

If there are any doubts???

# 555 Treatment Advances for Multiple Myeloma Have Disproportionally Benefited Patients Who Are Young, White, and

Have Higher Socioeconomic Status

If there is no Hope…

#4724

Thank you for your attention

• BTK expressed in MM plasma cells

• BTK is expressesd on osteoclasts but not osteoblasts

• Ibritunib inhibited OC activity in vitro and in animal

Ravi Vij, ASH 2014

Ibrutinib +/- dex in Pts with relapsed/ refractory MM: preliminary results phase 2

Pomalidomide, Bortezomib and Dexamethasone (PVD) for Patients with Relapsed Lenalidomide Refractory Multiple Myeloma (MM):

results of the phase 1

Lacy, MQ et al. Pomalidomide, Bortezomib and Dexamethasone (PVD) for Patients with Relapsed Lenalidomide Refractory Multiple Myeloma (MM). ASH 2014, abstract #304

Abstract 304, Martha Q. Lacy et al.

• N=47 • Refractory to Len • Median previous tt: 2

N=47

Response Rate, %

No. of

Responders

sCR

CR

VGPR

PR

85

40

3

6

12

19

Median PFS, mos 10.7

(95%CI: 9.4-18.5)

Median DOR 13.7 mo

(95%CI: 8.5-16.8)

21% ≥

VGPR

# 177, S Knop

Response to RAD in Newly DM is Independent of Cytogenetic Risk and Retained after Double Stem Cell Transplantation

• Phase 2, n= 190 • 163 completed RADx4/ 47 allo/ 60/ ASCTX2 • Results

• > VGPR 47,9% post RAD 60,6% post ASCT • Response independent to cytogentic t(4,14) and del 17P