Imedex 2-27-14

• Frontline Therapy and Maintenance for Newly Diagnosed Multiple Myeloma

– Transplant eligible vs transplant ineligible– Doublets vs triplets– Integrating Novel Agents into Frontline Therapy

• Carfilzomib• Elotuzumab• Pomalidomide• Oral PI’s

– Maintenance

Myeloma Survival by Decade

Current OS and High Risk Myeloma

A good risk stratification system should allow identification of this ~25% patients

Current Paradigm of Initial Treatment

The Concept of Dividing Myeloma Patients into Transplant Eligible vs Transplant

Ineligible

• Arguments for making this distinction:– The use of melphalan impedes the ability to collect PBSC’s– Older patients cannot tolerate more aggressive regimens– Older patients don’t need to achieve a deeper response

since they don’t have as long to live anyway

• Arguments against making this distinction:– More and more we have been able to collect stem cells after

melphalan– There are data that older patients benefit just as much from

deeper responses and would appreciate the added longevity (I would)

– Most US oncologists don’t use melphalan-based regimens anyway (prefer Vd and Rd)

Should CR be Our Goal in All Patients

Martinez-Lopez et al Blood. 2011;118(3):529-534

Prognostic effect of Patients in CR vs those in (nCR or VGPR or PR) vs those with (SD or PD) after

HDT/ASCT

In non-transplant candidates, achievement of CR is also associated with improved

PFS and OS

Gay F et al. Blood. 2011;117:3025.

Shouldn’t the achievement of deeper response be also a goal in non-transplant candidates?

PFS

Frontline TherapyTransplant Eligible Patients

Are Triplets the Standard of Care?

Improving Response Rates with Combination Therapies

Frontline TherapyTransplant Ineligible Patients

Increasing Options

Initial Treatment of Transplant - Ineligible Candidates

Continue initial therapy?

Initial therapy Maintenance?

Duration?

MP-based regimens MPT > MP

VMP > MP VMP = VTP

MPR-R>MPR=MP VMPT> VMP

Duration?

First Trial:MPT vs Rd vs Rd Continuous

Plenary

FIRST: Lenalidomide/Dexamethasone vs MPT in NDDM SCT-Ineligible Patients[1]

Ran

dom

izat

ion

1:1:

1

Arm BRd18

Arm CMPT

Len + LoDex 18 cycles (72 wks) Lenalidomide 25 mg Days 1-21/28LoDex 40 mg Days 1, 8, 15, 22/28

Mel + Pred + Thal 12 cycles[2] (72 wks)Melphalan 0.25 mg/kg Days 1-4/42Prednisone 2 mg/kg Days 1-4/42Thalidomide 200 mg Days 1-42/42

PD

, OS

, and

subs

eque

nt a

nti-M

M T

x

PD

or

unac

cept

able

toxi

city

Active treatment + PFS follow-up phase

Pts > 75 yrs: LoDex 20 mg Days 1, 8, 15, 22/28; Thal[3] 100 mg Days 1-42/42; Mel[3] 0.2 mg/kg Days 1-4. Stratification: age, country, and ISS stage.

Len + LoDex ContinuouslyLenalidomide 25 mg Days 1-21/28LoDex 40 mg Days 1, 8, 15, 22/28

Arm AContinuous Rd

1. Facon T, et al. ASH 2013. Abstract 2. 2. Facon T, et al. Lancet. 2007;370:1209-1218. 3. Hulin C, et al. J Clin Oncol. 2009;27:3664-3670.

Phase IIIN = 1623

FIRST Trial: Progression-Free Survival

Median PFS

Rd (n = 535)

25.5 mos

Rd18 (n = 541)

20.7 mos

MPT (n = 547)

21.2 mos

HR: Rd vs MPT: 0.72 (P = .00006) Rd vs Rd18: 0.70 (P = .00001) Rd18 vs MPT: 1.03 (P = .70349)

Mos

Pat

ien

ts (

%)

100

80

60

40

20

00 6 12 18 24 30 36 42 48 54 60

72 w

ks

1. Facon T, et al. ASH 2013. Abstract 2. Reproduced with permission.

Integrating Approved Newer Agents into Frontline Regimens

Transplant Eligible

Cycles 1–8• CFZ 20-27-36 mg/m2 Days

1–2, 8–9, 15–161

• LEN 25 mg Days 1–21• DEX 40 mg weekly

Cycles 1-4, 20 mg weekly Cycles 5–8

Carfilzomib, Lenalidomide, dexamethasone (CRd) Treatment Schema

Jakubowiak AJ, et al. Blood. 2012;120(9):1801-1809.

Stem cell collection

≥PR

CRd Cycles 9–24

CRdInduction

CRdMaintenance

CRd Cycles 1–4 CRd Cycles 5–8

ASCT

LEN Cycles 25+

Lenalidomide (off protocol)

Transplant-eligible

Transplant-eligible and --ineligible patients

Until disease progression or unacceptable toxicity

Cycles 9–24• CFZ on Days 1–2 and

15–16 only• CFZ, LEN, DEX at last

best tolerated doses

Cycles 25+• LEN at last best

tolerated dose

CRd - Best Response (n=53)*

*ITT, including patients who discontinued treatment early (eg, proceed to transplant)†iCR is an estimate of MRD-negative disease (10 color flow), based on percentage of patients in sCR evaluated for MRD at 12 months (18 of 19) and at 22 months (22 of 24)

†

Jakubowiak et al, ASCO 2013

CRd – Survival

N=53Median follow-up of 25 months (range 5-37)

Jakubowiak et al, ASCO 2013

0 5 10 15 20 25 30 35 400.0

0.2

0.4

0.6

0.8

1.0

Months

PF

S P

rob

abil

ity

0 10 20 30 400.0

0.2

0.4

0.6

0.8

1.0

Months

Su

rviv

al P

rob

abil

ity 24-month rate 98%

24-month rate 94%

Progression-free Survival Overall Survival

Patients receive 8 cycles of CRd Induction then 16 cycles of CRd maintenance then LEN maintenance until progression

CRd - Time to Response

0 4 8 12 16 20 24 28 32

0.0

0.2

0.4

0.6

0.8

1.0

PR

CR

nCR

VGPR

Months

Pro

ba

bili

ty

sCR

Median Time to Response, mo0.9 3.7

6.7 11.0 13.1

Jakubowiak et al, ASCO 2013

Integrating Approved Newer Agents into Frontline Regimens

Transplant Ineligible Patients

Carfilzomib, Melphalan, Prednisone (CMP)

MTD defined at CFZ 36 mg/m2Patients receive 9 cycles then stop treatment

68 patients have been enrolled in Phase 1 +2 Median age 72 years (61 – 86)High risk 17%After a median of 7 cycles (1 – 9)CR 6%VGPR 50% PR 35%SD 9%PD 0

Moreau et al, ASCO 2013, Courtesy P. Moreau

>VGPR 56%

93.9%

PFS

OS

Median follow-up = 12 months

>PR 91%

Median PFS = 22 months

OS= 87%

Carfilzomib, Cyclophosphamide, dex (CCd)

Time to EventProgression-Free and Overall Survival

Time (months)

Pat

ien

ts (

%)

0.00

0.25

0.50

0.75

1.00

0.0 2.5 5.0 7.5 10.0 12.5 15.0

Time (months)

Pat

ien

ts (

%)

0.00

0.25

0.50

0.75

1.00

0.0 2.5 5.0 7.5 10.0 12.5 15.0

0.00

0.25

0.50

0.75

1.00

0.0 2.5 5.0 7.5 10.0 12.5 15.0

0.00

0.25

0.50

0.75

1.00

0.0 2.5 5.0 7.5 10.0 12.5 15.0

1-year PFS

88%

1-year PFS

88%

0.00

0.25

0.50

0.75

1.00

0.0 2.5 5.0 7.5 10.0 12.5 15.0

Time (months)

0.00

0.25

0.50

0.75

1.00

0.0 2.5 5.0 7.5 10.0 12.5 15.0

Time (months)

1-year OS

87%

1-year OS

87%

PFS OS

Palumbo et al, ASH 2012, Courtesy A. Palumbo

Patients receive 9 cycles of CCD then CFZ maintenance until progression

Yet to be Approved New Agents with Potential

Ixazomib (weekly), Lenalidomide, dexamethasone

Patients treated at RP2D (2.23 mg/m2 / 4.0 mg)

4537 32

30

26 35

1932 23

0

10

20

30

40

50

60

70

80

90

100

After 4 cycles(n=47)

After 8 cycles(n=19)

Overall(n=52)

CRVGPRPR

%

≥VGPR58%

≥VGPR49% ≥VGPR

58%

Of 3 response-evaluable patients who completed 12 cycles, 2 achieved CR and 1 VGPR

ORR 94% ORR 95% ORR 90%

Kumar et al, ASH 2012, Courtesy S. Kumar

Oprozomib (ONX 0912)

• Oprozomib (OPZ, formerly ONX 0912) is a structural analog of carfilzomib (CFZ)

– It is an orally bioavailable, next-generation PI

– Similar to CFZ, OPZ is a potent, selective, and irreversible proteasome inhibitor

• Being evaluated in hematologic malignancies and solid tumors

Savona MR, et al. Blood. 2012;120. Abstract 203.

Monoclonal antibodies

• Anti CS 1– Elotuzumab

• Anti CD 38– Daratumumab – SAR 650984

Elotuzumab 10 mg/kg

Elotuzumab 20 mg/kg Total

Patients, n 36 37 73

ORR (≥PR), n (%) 33 (92) 28 (76) 61 (84)

CR/stringent CR, n (%) 5 (14) 4 (11) 9 (12)

VGPR, n (%) 17 (47) 13 (35) 30 (41)

PR, n (%) 11 (31) 11 (30) 22 (30)

<PR, n (%) 3 (8) 9 (24) 12 (16)

Efficacy: Best ResponsePhase II (Study 1703)

1. Lonial S et al. Blood 2011;Abstract 303

• Overall median time to response: 1 mo (range, 0.7-19.2); 1 new and 3 deepening responses were observed since the previous data cut (October, 2011)1

• Overall median time to best response: 2.5 mo (range, 0.7-21.4)

• Median duration of objective response: 15 mo

Progression-free Survival from the Phase II Cohort

10 mg/kg (n=36): 33 mos (95% CI:14.883-NA)20 mg/kg (n=37): 18.6 mos (95% CI: 12.912-32.361)Total (n=73): 25.8 mos (95% CI: 15.376-35.713)

In the 10 mg/kg cohort, median PFS was 33 months In the 20 mg/kg cohort, the median PFS was 18 months

Lonial et al, ASCO 2013

Ongoing Studies with Elotuzumab

Phase Treatment Primary Endpoint

MM Patient Population

ELOQUENT - 1 IIIRD +/– Elotuzumab

PFSPreviously Untreated

ELOQUENT - 2 IIIRD +/– Elotuzumab

PFSRelapsed or Refractory

http://www.clinicaltrial.gov/ct2/show/NCT01239797http://www.clinicaltrial.gov/ct2/show/NCT01335399

Daratumumab Phase I/IIMaximal Change in Paraprotein

≤1 mg/kg 2 mg/kg 4 mg/kg 8 mg/kg 16 mg/kg

• Data at baseline below limits for measurable disease

Results are before database lock

*

SAR650984: Maximal Change in Paraprotein

Myeloma Patients Treated at Doses of 1 mg/kg Q2W or Higher

One patient at 3.0 mg/kg and 20 mg/kg with 0% change; One patient at 20 mg/kg not evaluable

5 mg/kg Q2W10 mg/kg Q2W10 mg/kg QW20 mg/kg Q2W

3 mg/kg Q2W1 mg/kg Q2W

-100

% C

han

ge

in P

arap

rote

in

-75

-50

-25

0

25

50

75

100

125

150

Stem Cell Transplantation

Conventional Chemotherapy vs ASCT RANDOMIZED STUDIES

Median OS

Patients(n) Age

Median Follow

UpConventional

Chemotherapy ASCT

IFM90[1] 200 <65 7 y 44 57

MAG91[2] 190 55-65 56 m 50 55

MRC7[3] 403 <65 42 m 42 55

PETHEMA[4]* 164 <65 42 m 64 72

1. Attal M et al. N Engl J Med. 1996;335:91.2. Fermand JP et al. J Clin Oncol. 2005;23:9227.

3. Child A et al. N Engl J Med. 2003;348:1875.4. Blade J et al. Blood. 2005;106:3755.

*in patients responding to conventional chemotherapy

Len-Bz-Dex ×3

Len-Bz-Dex ×5

Len ×12m (IFM)

Len until relpase (US

Stem collection

Len-Bz-Dex ×3

ASCT

Len ×12m (IFM)Len until relapse (US)

Stem collection

Len-Bz-Dex ×2

ASCT at relapse

NCI Clinical Trial Identifier NCT01191060.

The Debate…ASCT:Up-Front or at Relapse

Maintenance Therapy

Not as Simple as We Thought

ITT Analysis with a median follow-up from transplant of ~48 months p<0.001 Median TTP: 50 months versus 27 months.

146 events on placebo104 events on lenalidomide

Post-Transplant Lenalidomide MaintenanceCALGB 100104

Estimated HR=0.51 (95% CI = 0.39 to 0.66),

McCarthy, IMW Kyoto, April 2013

Updated TTP Updated OSIncludes pts crossing over

Analysis including placebo patients crossing over within 12 months of randomization on lenalidomide arm with a median follow-up of ~48 months. p= 0.003

Cut-off date January 7, 2013

CALGB 100104: Event-Free Survival & SPM

ASCT: autologous stem cell transplant; CALGB: Cancer and Leukemia Group B; EFS: event-free survival; HR: hazard ratio; LEN: lenalidomide; N/A: not applicable; PBO: placebo; PD: progressive disease; SPM: second primary malignancy.

McCarthy PL. N Engl J Med. 2012;366:1770-1781.

•

– Hematologic SPM: 8 (LEN; 3.5%) vs. 1 (PBO; 0.4%)

– Solid-tumor SPM: 10 (LEN; 4.3%) vs. 5 (PBO; 2.2%)

IFM 2005-02: Progression-Free Survival

ASCT: autologous stem cell transplant; β2-M: β2-microglobulin; del: deletion; HR: hazard ratio; IFM: Intergroupe Francophone du Myélome; LEN: lenalidomide; PBO: placebo; PFS: progression-free survival; VGPR: very good partial response.

Attal M. N Engl J Med. 2012;366:1782-1791

IFM 2005-02: Overall Survival

• With a median follow-up of 45 months, no differences in OS has been observed across treatment arms

– 4 year OS (post-randomization): 73% (LEN) vs. 75% (placebo)

IFM: Intergroupe Francophone du Myélome; LEN: lenalidomide; N/A: not applicable; OS: overall survival; PBO: placebo.

Attal M. N Engl J Med. 2012;366:1782-1791

IFM 2005-02: Event-Free Survival & SPM*

* Data as of Oct 2011, including events during consolidation and maintenance.

EFS: event-free survival; IFM: Intergroupe Francophone du Myélome; LEN: lenalidomide; N/A: not applicable; PBO: placebo; PD: progressive disease; SPM: second primary malignancy.

Attal M. N Engl J Med. 2012;366:1782-1791

– Hematologic SPM: 13 (LEN) vs. 5 (placebo) (18 v 7)

– Solid tumor SPM: 10 (LEN) vs. 4 (placebo) (13 v 11)

Bortezomib MaintenanceHOVON-65/GMMG-HD4 Trial

PFS OS

Sonneveld et al, J Clin Oncol 2012;30:2946-55

Bortezomib was used both pre- and post-transplantBenefits mostly in patients with high risk disease

MM-015: Study Design

Dex: dexamethasone; ISS: International Staging System; MP: melphalan-prednisone; MPR: melphalan-prednisone-lenalidomide; MPR-R: melphalan-prednisone-lenalidomide followed by lenalidomide maintenance; PBO: placebo; po: orally.

Palumbo A. N Engl J Med. 2012;366:1759-1769.

MM-015: Progression-Free Survival

HR: hazard ratio; MP: melphalan-prednisone; MPR: melphalan-prednisone-lenalidomide; MPR-R: melphalan-prednisone-lenalidomide followed by lenalidomide maintenance; N/A: not applicable; PFS: progression-free survival.

Palumbo A. N Engl J Med. 2012;366:1759-1769.

• MPR-R significantly extended median PFS vs. MP and MPR

MM-015: Overall Survival

HR: hazard ratio; MP: melphalan-prednisone; MPR: melphalan-prednisone-lenalidomide; MPR-R: melphalan-prednisone-lenalidomide followed by lenalidomide maintenance; N/A: not applicable; OS: overall survival.

Palumbo A. N Engl J Med. 2012;366:1759-1769.

• The number of deaths is low and comparable across treatment groups

Controversies in Maintenance Therapy

• Should everyone (anyone) receive it?• Should everyone receive the same drug(s)?

– Lenalidomide?– VRd for high risk? Who is high risk?

• What should be the duration of therapy– Is there a way to measure this (MRD)?– Does more therapy result in more SPM’s and less

effect?• Would some patients be better off with just

“consolidation?”• At least those of us who work in this area will

not be at a loss for new studies.