Ludwig© 2013

Heinz LudwigDepartment of Medicine I

Center for Oncology, Hematology and Palliative CareWilhelminenhospital, Vienna, Austria

What we know about myeloma in elderly patients from trials and observational

studies?

Ludwig© 2013

Rapid symptom control

Optimal quality of life

Few and acceptable side effects

Best possible quality of response

Long PFS

Long OS

Cure ?

Goals of therapy in elderly patients

Ludwig© 2013

1-drug* 2 - drugs 3- drugs 4 - drugs

Dex Bendamustine+P

MPT VMPT

Thal VD VMP

MP* CTD

Thal-Dex VTD

L-ldDex

Most commonly used combinations contain 2-3 drugs

*only exceptional cases

Drug combinations for elderly patients

Possible options

H. Ludwig 2013

Characteristics of the Elderly Patient Chronological age does not necessarily correlate with biological age

The variation in biological fitness in a specific age cohort increases with rising age, but the ‚biology‘ of myeloma cells does not vary with age

All three individuals are 70 years old

Fit Minor morbidity significant morbidity

Ludwig© 2013

Assess fraility

Fit Unfit Frail

Full go

Slow go

Very slow go

2 or 3 drug regimen

reduce dose 2 (3) drug regimen

further dose reduction MP, CTX-P

VD, Ld

Treatment of patients with multiple myeloma not eligible for transplantation

H. Ludwig 2013

Instruments for assessing fraility and allocation to treatment groups

Fit Unfit Frail

Age <80 yr Fit >80 yr Unfit >80 yr

ADL 6

IADL 8

Charlson 0

ADL 5

IADL 6-7

Charlson 1

ADL ≤4

IADL ≤5

Charlson ≥2

Go-go Moderate-go Slow-go

Full-dose

regimens

Dose level 0

Reduced-dose

regimens

Dose level -1

Reduced-dose

Palliative

approach

Dose level -2

Palumbo A et al. IMW 2013

AssessAgeADLIADLCharlson comorbidity score

H. Ludwig 2013

Adaptation of dose according to risk factors

Agent Dose level 0 Dose level-1 Dose level - 2

Dexamethasone 40 mg 20 mg 10 mg

Melphalan0.25 mg/kg or 9

mg/m2

0.18 mg/kg or 7.5 mg/m2

0.13 mg/kg or 5 mg/m2

Thalidomide 100 mg 50 mg 50 mg/qod

Lenalidomide 25 mg 15 mg 10 mg

Bortezomib1.3 mg twice weekly, sc

1.3 mg weekly, sc1.0 mg weekly,

sc

Prednisone 60 mg/m2 30 mg/m2 15 mg/m2

Cyclophosphamide 100 mg 50 mg 50 mg/qod

Palumbo et al.,BLOOD 2011Palumbo et al.,BLOOD 2011

H. Ludwig 2013

Polyneuropathy Avoid bortezomib (or use once weekly sc)

Renal impairment Consider dose adaptations when using lenalidomide

Bone marrow insufficiencyCareful dosing of cytoreductive drugs, consider single agent dexamethasone

Cardiac arrhythmias/

dysfunctionCave: Thalidomide & high dose dexamethasone

Immune system Careful dosing of cytoreductive drugs

Diabetes Cave: high dose dexamethasone

Cognitive function/compliance

Consider iv regimens

Comorbidities relevant for treatment selection in myeloma

H. Ludwig 2013

Higher risk of mortality in patients ≥ 75 years of age

• Median follow up 33 months

• Median OS in total population 50 months

• Estimated 3-year OS 68% in patients < 75 years of age vs 57% in patients ≥ 75 years of age (HR 1.44, CI 1.20-1.72, p < 0.001)

Bringhen S, et al. Haematologica. 2013;98:980-7.

Retrospective meta-analysis of 4 EU phase III trials (N = 1,435) with MP, MPT, VMP, and VMPT

HR (95% CI) p value

All 1.44 (1.20–0.72) < 0.001

MP 1.21 (0.90–1.64) 0.21

MPT 1.12 (0.81–1.56) 0.49

VMP 1.62 (1.04–2.52) 0.03

VTP/VMPT 3.02 (1.86–4.90) < 0.001

Higher mortality in patients ≥ 75 years of age

1 100.1

Higher mortality in patients < 75 years of age

Ludwig© 2013

• n=1435 (≥ 65 yrs ): MPT vs MP, VMP vs MP, VMP vs VMPT-VT

Bringhen et al. Haematologica 2013;98(6):980-987

Age and Organ Damage Correlate with Poor OS: Meta-analysis of 4 Randomized Trials

H. Ludwig 2013

New Regimen Comparator Outcome

MPT (6 Trials)* vs. MP MPT PFS 5/6, OS 2/6

CTDa vs. MP CTDa ORR

VMP vs. MP VMP PFS, OS

VMPT VT vs. VMP VMPT VT

PFS. OS

VMP VT or VP VDT VT or VP

ns

MPR R vs. MPR

or MP

MPR R

PFS

LD vs. Ld Ld PFS, OS

LD continous vs. Ld x 18, vs MPT x 12

Ld cont PFS, OS

*Meta-analysis of the 6 trials: PFS () OS

Phase III studies incorporating novel agents in the non-transplant setting

H. Ludwig 2013

MPT vs MP: Meta-analysis of 1685 individual-patient data of 6 randomized trials

Fayers et al. Blood 2011, accepted for publication 30 May 2011

0.0

0.2

0.4

0.6

0.8

1.0

Su

rviv

al p

rop

ort

ion

0 12 24 36 48

months

MPMPT

Median 14.9 mos (14.0-16.6)

Median 20.3 mos (18.8-21.6)

HR=0.67 in favor of MPT, p<0.0001

PFS

0.0

0.2

0.4

0.6

0.8

1.0

0 12 24 36 48months

Median 32.7 mos (30.5-36.6)

Median 39.3 mos(35.6-44.6)

HR=0.83 in favor of MPT, p=0.005*

OS

*Cox model for treatment, with analysis stratified by study using a random effects (frailty) model

MPMPT

H. Ludwig 2013

MPT: Pros and Cons

Pros

Survival benefit

Oral regimen

Not expensive

Cons

Thalidomide toxicity

Suboptimal in cytogenetic high risk

group

Shorter survival after relapse

H. Ludwig 2013

MP vs. VMP (VISTA) Final updated OS analysis

Median follow-up 60.1 months

•31% reduced risk of death

Median OS benefit: 13.3 months5-year OS rates: 46.0% vs 34.4%

100

90

80

70

60

50

40

30

20

10

0

Patie

nts

aliv

e (%

)

0 6 12 18 24 30 36 42 48 54 60 66 72 78Time (months)

Group N Event Median HR (95% CI) P-value

M 338 211 43.1

VMP 344 176 56.4 0.695 (0.567, 0.852) 0.0004

San Miguel et al. JCO 2013

H. Ludwig 2013San Miguel et al., JCO 2013

Overall survival in different subgroups: VMP vs. MP

H. Ludwig 2013

Time to next therapyTime to progression

Treatment-free interval Overall survival

Harousseau JL et al., BLOOD 2010

VMP induced CR is associated with improved outcome

H. Ludwig 2013

VD vs. VTD vs. VMP followed by bortezomib maintenance therapy

Niesvitzky R. et al., BLOO, 116 2010

Para-meter

VD VTD VMP

>VGPR 36% 44% 40%

ORR 68% 78% 71%

PNP G3-4

15% 26% 20%

PFS (mos)

13.8 18.4 17.3

H. Ludwig 2013

Global QoL during VD, VTD and VMP induction therapy

Niesvizky R et al., ASH 2011

VD vs. VTD or VMP: shorter PFS, similar OS, better tolerance

H. Ludwig 2013

VMPCycles 1-9Bortezomib 1.3 mg/m2 IV: days 1,8,15,22*Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4

VMPTCycles 1-9Bortezomib 1.3 mg/m2 IV: days 1,8,15,22*Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4Thalidomide 50 mg/day continuously

RANDOMIZE

9 x 5-week cycles in both arms

511 patients (older than 65 years) randomized from 58 Italian centers

Patients: Symptomatic multiple myeloma/end organ damage with measurable disease

≥65 yrs or <65 yrs and not transplant-eligible; creatinine ≤ 2.5 mg/dL

Treatment scheduleTreatment schedule

MAINTENANCEBortezomib 1.3 mg/m2 IV: days 1,15Thalidomide 50 mg/day continuously

NO MAINTENANCE

Until relapse

* 66 VMP patients and 73 VMPT patients were treated with twice weekly infusions of Bortezomib

Treatment schedule

H. Ludwig 2013Palumbo A et al. ASH 2012

Progression free survival Overall survivallandmark analysis

PFS and OS: VMP vs VMPT –VT

H. Ludwig 2013

Age < 75 years

HR 0.76, 95% CI, 0.42-1.37, p =.36

Age ≥ 75 years

HR 0.60, 95% CI, 0.41-0.89, p=0.009 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 60 700.00

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

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

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

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

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

ISS 3 VGPR/PR

ISS 1-2 CR

HR 0.66, 95% CI, 0.43-1.00, p =.05

HR 0.64, 95% CI, 0.31-1.31, p =.22

HR 0.45, 95% CI, 0.24-0.86, p =.01

HR 0.80, 95% CI, 0.54-1.20, p =.28

Off therapyVT maint. VMPT

VMP No maint.Off therapy

VT maint. VMPT

VMP No maint.No maint.Off therapy

VT maint. VMPT

VMP No maint.Off therapy

VT maint. VMPT

VMP No maint.No maint.Off therapy

VT maint. VMPT

VMP No maint.Off therapy

VT maint. VMPT

VMP No maint.No maint.

Overall survival Landmark analysis

Overall survival Landmark analysisOverall survival, Landmark analysis

H. Ludwig 2013

Overall survival from relapseOverall survival from relapse

HR 0.92, 95% CI, 0.66-1.28, p =.630.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50 60

HR 0.92, 95% CI, 0.66-1.28, p =.630.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50 60

Pat

ien

ts (

%)

Time (months)

3-years OS Median OS

VMP

VMPT-VT

46% 27.3 months

47% 27.8 months

3-years OS Median OS

VMP

VMPT-VT

46% 27.3 months

47% 27.8 months

Palumbo et al. ASH 2012 (Abstract 200)

Overall survival from relapse

H. Ludwig 2013

VMPT-VT versus VMP in newly diagnosed elderly patients

• Significant OS benefit in patients

– < 75 years of age (none in pts > 75 years)

– With stage ISS 1-2 (tendency for OS in stage ISS 3)

– With CR (none in pts with VGPR/PR)

• Benefit in ‚good risk‘ patients with CR only

• Grade 3- 4 adverse events during VT maintenance

– PN 7%

– Hematological toxicity 5%

– Infection 3%

– Discontinuation due to AEs 12%

Palumbo et al. ASH 2012 (Abstract 200), oral presentation

H. Ludwig 2013

How to reduce toxicity of Bortezomib and and maintain efficacy?

Bortezomib once weekly

longer duration of therapy

similar cumulative dose

similar efficacy

less toxicty (G3/4 neurotoxicity)

Bortezomib subcutaneously

10 times lower serum peak concentration

similar area under the curve

less neurotoxicity

similar efficacy

H. Ludwig 2013

-

•Stratified by age (<75 years vs > 75 years) and stage (ISS I/II vs III)

• -ISS, International Staging System; MP, melphalan, prednisone; MPR, melphalan, prednisone, lenalidomide; MPR-R, melphalan, prednisone, lenalidomidewith lenalidomidemaintenance; PBO, placebo.

MP

M: 0.18 mg/kg, days 1-4

P: 2 mg/kg, days 1-4

PBO: days 1-21

MPR

M: 0.18 mg/kg, days 1-4P: 2 mg/kg, days 1-4

R: 10 mg/day po, days 1-21Placebo

Placebo

MPR-R

M: 0.18 mg/kg, days 1-4

P: 2 mg/kg, days 1-4R: 10 mg/day po, days 1-21

RA

ND

OM

IZA

TIO

N

Double-blind Treatment Phase

DiseaseProgression

Maintenance

Lenalidomide

(25 mg/day) +/-

Dexamethasone

Open-Label Extension Phase

Lenalidomide10 mg/daydays 1-21

Cycles (28-day) 1-9 Cycles 10+

N = 459, 82 centers in Europe, Australia, and Israel

MPR-R vs. MPR vs. MP (MM015 trial)

H. Ludwig 2013

0

HR, hazard ratio; MP, melphalan, prednisone; MPR, melphalan, prednisone, lenalidomide ; MPR -R, melphalan, prednisone, lenalidomidewith lenalidomidemaintenance; OS, overall survival; PFS, progression- free survival; TTP, time to progression.

Progression-Free and Overall SurvivalAll Patients

• TTP HR advantages were similar: MPR- R vs MP = 0.337; MPR vs MP = 0.826

Time (Months)

Pat

ien

ts (

%)

HR 0.395 P < .001

HR 0.796P = .135

0 10 20 30 400

25

50

75

100

Median PFS

MPR-R 31 months

MPR 14 months

MP 13 months

Median PFS

MPR-R 31 months

MPR 14 months

MP 13 months

0 20 30 40 50 60

4-year OS

MPR-R 59%

MPR 58%

MP 58%

4-year OS

MPR-R 59%

MPR 58%

MP 58%

Pat

ien

ts (

%)

25

50

75

10

100

HR 0.898 P = .579

HR 1.089P = .648

Time (Months)

Progression-free and overall survival

H. Ludwig 2013

HR, hazard ratio; MP, melphalan, prednisone; MPR, melphalan, prednisone, lenalidomide; MPR-R, melphalan, prednisone, lenalidomide with lenalidomide maintenance; OS, overall survival; PFS, progression-free survival.

PFS and OS With MPRPFS and OS With MPR--R and MPRR and MPRPatients Aged 65Patients Aged 65--75 Years75 Years

Time (Months)

Pa

tien

ts (

%)

0 10 20 30 400

25

50

75

100

Median PFS

MPR-R 31 months

MPR 15 months

MP 12 months

Median PFS

MPR-R 31 months

MPR 15 months

MP 12 months

HR 0.301 P < .001

HR 0.618P = .006

0 10 20 30 40 50 600

25

50

75

100

Time (Months)

Pa

tien

ts (

%)

4-Year OS

MPR-R 69%

MPR 61%

MP 58%

4-Year OS

MPR-R 69%

MPR 61%

MP 58%

HR 0.706 P = .133

HR 0.902P = .639

PFS and OS with MPR-R and MPR patients aged 65-75 years

H. Ludwig 2013

FIRST: Phase 3 trial of Lenalidomide + low-dose Dex vs MPT (IFM 07-01; MM-020)

Inclusion criteriaN = 1,623

•Previously untreated MM

•Age 65 years or not eligible for a transplant

•No neuropathy of grade > 2

Rd (28-day cycle; until disease progression)Lenalidomide 25 mg/day, days 1–21 Dexamethasone* 40 mg/day, days 1, 8, 15, and 22

Rd (28-day cycle; until disease progression)Lenalidomide 25 mg/day, days 1–21 Dexamethasone* 40 mg/day, days 1, 8, 15, and 22

Rd (28-day cycle; up to 18 cycles)Lenalidomide 25 mg/day, days 1–21 Dexamethasone* 40 mg/day, days 1, 8, 15, and 22

Rd (28-day cycle; up to 18 cycles)Lenalidomide 25 mg/day, days 1–21 Dexamethasone* 40 mg/day, days 1, 8, 15, and 22

Centres in EU, Switzerland, APAC, USA, and Canada

*In patients aged > 75 years: Dex 20 mg/day, melphalan 0.20 mg/kg/day, thalidomide 100 mg/day

MPT (6-week cycle; up to 12 cycles )Melphalan* 0.25 mg/kg/day, days 1–4Prednisone 2.0 mg/kg/day, days 1–4Thalidomide* 200 mg/day

MPT (6-week cycle; up to 12 cycles )Melphalan* 0.25 mg/kg/day, days 1–4Prednisone 2.0 mg/kg/day, days 1–4Thalidomide* 200 mg/day

Primary end-point: PFS

NCT00689936. Available from: www.clinicaltrials.gov.

RANDOMIZATION

H. Ludwig 2013

Trials & duration of therapy (months)

VMP (Vista) 12

MPT trials 6-18.5

CTDa 6-9

MPR-R 9, R untill PD

VMPT-VT 12.5, VT maintenance: 2 years

LD (MM20) Continously until PD/intolerance

Duration of therapy: minimally 6, maximally 12 monthsMost experts recommend ≈ 9 months

What is the optimal duration of first line therapy?

H. Ludwig 2013

CR rate (%) Median PFS (months) Median OS (months)

MP1,2 rare 11–20 29 - 43.45 - 49.42

BP2 - 14* 32

MPT3 10 20.3 39

CTDa4 13 13 33

VMP5 30 21.7–27.4 56.4

MPR-R6 10 31 59% (4-yr OS)

VMP-VT/VP7 42 35 58% (5-yr OS)

VMPT-VT8,9 42 35.3 59.3% (5-yr OS)

LD continuous10

≥PR 75% vs. 62%

28% ↓ risk for PD 22% ↓ risk for death

1MTCG. J Clin Oncol 1998;16(12):3832-422Ludwig et al., BLOOD 2009

2Pönisch et al. J Cancer Res Clin Oncol. 2006;132:205-12.3Fayers et al. Blood 2011; 118(5):1239-1247

4Morgan et al. Blood 2011;118:1231-8

5San Miguel et al. JCO 2013; 31(4): 448-4556Palumbo et al. N Engl J Med 2012;366(19):1759-69

7Mateos et al. Blood 2012; 120: 2581-25888Palumbo et al. ASH 2012 (Abstract 200), oral presentation9Palumbo et al. ASH 2011 (Abstract 653), oral presentation

10Facon et al. ASH 2013 (Abstract 2), oral presentation

Outcome with novel combinations

H. Ludwig 2013 Gay et al. Blood 2011; 117(11):3025-31

• Retrospective analysis: 3 randomized European trials of GIMEMA and HOVON groups (N=1175)

• First-line treatment

MP (n=332), MPT (n=332), VMP (n=257), VMPT-VT (n=254)

Significant benefit also seen when analysis is restricted to patients >75 years old

PFS OS

P<0.001 P<0.001

CR

VGPR

PR

CR

VGPR

PR

Pro

bab

ility

Pro

bab

ility

Hematologic CR correlates with long PFS and OS in elderly patients treated with novel agents

H. Ludwig 2013

100

80

60

40

20

PFS

Immunophenotypic CR 90% at 3y

“Stringent CR” 38% at 3y

Conventional CR 57% at 3y

PR (≥70% reduction) 28% at 3y

Paiva et al; J Clin Oncol. 2011;29(12):1627-33.

Immunophenotypc CR correlates with OS GEM2005 >65y

H. Ludwig 2013

Cytogenetic abnormalities are a major prognostic factor in elderly patients with MM: IFM experience

1,890 patients (median age 72, range 66–94), including 1,095 patients with updated data on treatment modalities and survival

1,890 patients (median age 72, range 66–94), including 1,095 patients with updated data on treatment modalities and survival

Whatever the treatment, t(4;14) and del(17p) were associated with shorter PFS and OS; similar results were achieved in the subgroup of 335 patients > 75 years

Whatever the treatment, t(4;14) and del(17p) were associated with shorter PFS and OS; similar results were achieved in the subgroup of 335 patients > 75 years

1. Avet-Loiseau H, et al. J Clin Oncol. 2013 31(22):2806-9. 2. Hulin et al. Blood 2012:[abstract 204].

0.50

1.00

0.75

0.25

0.00

Pro

bab

ilit

y o

f O

S

Time (years)1 2 3 4 50

OS according to t(4:14)

t(4:14) negt(4:14) pos

0.50

1.00

0.75

0.25

0.00

Pro

bab

ilit

y o

f O

S

Time (years)1 2 3 4 50

OS according to del(17p)

del(17p) < 60del(17p) ≥ 60

p < 10.4 p < 10.6

H. Ludwig 2013

The challenge of high-risk CA [t(4;14), del(17p), t(14;16)] in NDMM elderly patients

StudyNo of pts with high-risk CA

Outcome of high-risk CA patients

MPT/MP1 NR NR

CTDa/MP1

(MRC Myeloma IX)NR

CTDa does not overcome the effect of high-risk CA and is not significantly better than MP in high-risk CA

RD/Rd2 (E4A03) 21 2y OS=76% for high-risk CA vs 91%

VMP/MP3 (VISTA) 46Absence of OS benefit, median OS 44.1mo. VMP vs 50.6 mo., MP

VMP/VTP – VT/VP4

(GEM-05)44

Adverse prognosis of both t(4;14) and del (17p) regardless of induction and maintenance. Median OS t(4;14)=29 mo., del(17p) = 27mo.

First generation novel agents only partly overcome the negative prognosis of high-risk CA in newly diagnosed elderly patients with MM

First generation novel agents only partly overcome the negative prognosis of high-risk CA in newly diagnosed elderly patients with MM

1. Bergsagel PL, et al. Blood. 2013;121:884-91. 2. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. 3. San Miguel J, et al. J Clin Oncol. 2013;31:448-55. 4. Mateos MV, et al. Blood. 2011;118:4547-53.

H. Ludwig 2013

Thalidomide

PFS

no improvement in OS

Reduced OS after relapse

Negative impact on high risk pts

Clinical practice

recommendations50 mg for ≈ 12 mos may be considered

Lenalidomide PFS-no improvement in OS-increased risk for SPM

Bortezomib-thalidomide Tendency for PFS and OS but not

significant superior over VP

Maintenance studies - summary

H. Ludwig 2013

Summary: Treatment results in elderly patients

MPT, PFS, +/- OS, can be toxic in elderly pts

VMP, PFS OS, may induce severe PNP

Ld, PFS, OS, low dose Dex recommended

Thal-Dex, an option for fit pts

CTDa vs MP, overall response rate, CR, VGPR

Bendamustine-Pred, approved for first line TX

Thalidomide maintenance PFS, but not OS

MPR with Lenalidomide maintenance PFS, but not OS

VT maintenance not significantly better than VP

H. Ludwig 2013

Maintenance

The natural course of multiple myeloma

H. Ludwig 2013

Treatment of relapsed/refractory MMGeneral considerations

Components of initial therapy

– Alkylating-based

– Dexamethasone-based

– IMiD-based

– Bortezomib-based

Efficacy of initial therapy

– Quality of response

– Tolerance of tretament

– Duration of respose

Patient status and type of relapse

– Age, performance status, glucose

metabolism

– Aggressive vs non-aggressive

relapse

– Bone marrow reserve

– Renal function impairment

– Pre-existing peripheral

neuropathy

– Oral vs. iv therapy

IMiD, immunomodulatory derivative; MM, multiple myeloma

H. Ludwig 2013

Frontline Therapy successful?

Yes No

Long duration of response Select other TX (Class switch)

Yes No

Repeat first line TX Select other TX

Bortezomib based frontline TX:

IMiD based frontline TX

IMiD-based TD MPT CTD Rd (MPR)

Bort-based VD VMP VTD

Treatment of Relapsed/Refractory Myeloma

Old TypeMPDCEPM-100 +ASCT Ludwig et al.

The Oncologist 2011

Pomalidomide

H. Ludwig 2013

Retreatment with bortezomib: a meta-analysis including 23 studies

• 23 trials, 1051 patients

• Patients refractory or not refractory to bortezomib

• 11 studies including bortezomib-refractory pts

• 6 studies excluding bortezomib-refractory pts

• 6 studies missing information on bortezomib-refractory pts

• Combinations

• Bortezomib ± Dex: 4 studies

• Bortezomib + combination therapy: 19 studies

Knopf et al. IMW 2013 (Abstract P-228), poster presentation

H. Ludwig 2013

Results of meta-analysis of retreatement with bortezomib in different risk groups

Variable ORRTTP

(months)OS

(months)

Relapsed 57% 8.5 19.7

Relapsed/>refractory 19% 5.9 20.4

≤ 4 prior TX lines 43% 8.2 13.3

> 4 prior TX lines 29% 7.1 20.0

Boz + Dex 51% 7.9 19.2

Combination 36% 7.1 16.2

Pooled analysis 51% 8.4 19.2

Knopf et al., IMW 2013

H. Ludwig 2013

Carfilzomib a second generation proteasome inhibitor

H. Ludwig 2013

Single agent Carfilzomib in relapsed/refractory patients

Response category

All patients(n=267)

High risk cytogenetics(n=71)

CR 0.4% 0

VGPR 5.1% 4.2%

PR 18.3% 25.4%

MR 13.2% 4.2%

ORR 37% 29.5%

PFS(median) 3.7 mos 3.6 mos

DOR (median) 7.8 mos 6.9 mos

Progressive disease at enrollment, Relapsed from 2 prior TX lines, Must include bortezomib

Must include thalidomide or lenalidomide, Refractory to last line

Siegel D et al., BLOOD 2012

H. Ludwig 2013

Patients with relapsed/refractory myeloma(N = 455)

POM + LoDexPomalidomide 4 mg on Days 1-21 +

Dexamethasone 40 mg (if ≤ 75 yrs) or 20 mg (if > 75 yrs) on Days 1, 8, 15, 22

(n = 302)

HiDexDexamethasone 40 mg (if ≤ 75 yrs) or

20 mg (if > 75 yrs) on Days 1-4, 9-12, 17-20 (n = 153)

28-day cycles

Stratified by age (≤ 75 vs > 75 yrs), number of previous treatments (2 vs > 2), disease population (refractory vs relapsed/refractory vs intolerant/refractory)

Until PD*Companion trial

MM-003C: Pomalidomide

21/28 days

Follow-up for OS and SPM until 5 yrsPost enrollment

Until PD*

San Miguel JF, et al. ASCO 2013. Abstract 8510.

Pomalidomide + LoDex vs HiDex (MM-003): Phase III Trial Design

• Primary endpoint: PFS

• Secondary endpoints: OS, ORR, DOR, safety *Independently adjudicated in real time.Thromboprophylaxis indicated for patients receiving pomalidomide or with history of DVT.

H. Ludwig 2013

Pomalidomide + LoDex vs HiDex: Key Criteria for Pts With Relapsed/Refractory MM

• All patients

– Refractory to last therapy

– ≥ 2 previous therapies

• ≥ 2 consecutive cycles of lenalidomide and bortezomib (alone or in combination) or

adequate previous alkylator therapy

– Failed bortezomib and lenalidomide

• Progression within 60 days; PR with progression within 6 mos, and/or bortezomib

intolerant after ≥ 2 cycles and achieving ≤ MR

– Refractory or relapsed/refractory

• Primary refractory (never achieved better than PD to any therapy) or relapsed and

refractory (relapsed after having ≥ SD for ≥ 2 cycles of therapy to ≥ 1 previous regimen

and then developed PD ≤ 60 days of completing their last treatment)

San Miguel JF, et al. ASCO 2013. Abstract 8510.

H. Ludwig 2013

Mos

Pomalidomide + LoDex vs HiDex (MM-003)

PFS (ITT Population) OS (ITT Population)

Mos

San Miguel JF, et al. ASCO 2013. Abstract 8510.

H. Ludwig 2013

Pomalidomide + LoDex vs HiDex Adverse Events (MM-003)

AE, % POM + LoDex(n = 300)

HiDex(n = 150)

Grade 3/4 hematologic AEs

Neutropenia 48 16

Anemia 33 37

Thrombocytopenia 22 26

Grade 3/4 nonhematologic AEs

Infections 30 24

– Pneumonia 13 8

Bone pain 7 5

Fatigue 5 6

Asthenia 4 6

Grade 3/4 AEs of interest

DVT/PE 1 0

Peripheral neuropathy* 1 1

Discontinuation due to AEs 9 10

*Includes hyperesthesia, peripheral sensory neuropathy, paraesthesia, hypoesthesia, and polyneuropathy.

San Miguel JF, et al. ASCO 2013. Abstract 8510.

H. Ludwig 2013

Zoledronic Acid vs Clodronate in Newly Diagnosed MM: SREs

Morgan GJ, et al. ASH 2010. Abstract 311.

• Significantly reduced incidence of SREs* with zoledronic acid vs clodronate

– Regardless of presence of bone lesions at baseline

HR: 0.74 (P = .0004)

*SREs defined as vertebral fractures, other fractures, spinal cord compression, and the requirement for radiation or surgery to bone lesions or the appearance of new osteolytic bone lesions.

Patients at Risk, n

0

10

20

30

ZOL

Pat

ien

ts W

ith

an

S

RE

(%

)

CLO981979

390337

284256

0 18 24

ZOL

Time From Randomization (Mos)

CLO40

138112

36

9774

42

663629

6

201173

30

506465

12

35.3%

27.0%

H. Ludwig 2013

Planned and/or ongoing studies

VD vs VTD vs VMP + V maintenance (UPFRONT study)

VRd vs Rd + Rd maintenance (SWOG S0777)

Rd vs MPT vs Rd + Rd maintenance (MM20/IM(FIRST trial)

Rd vs MPR vs CRP + maintenance R vs RP (EMNTG)

MPT+T vs MPR+R (HOVON 87-NMSG 18, ECOG EA1A06)

CTDa vs RCD +/- R maintenance (MRC Myeloma XI)

VP vs VMP vs VCP + VP maintenance (EMNTG)

Carfilzomib + MP ((CARMYSAP trial): ORR of 92% (40% VGPR). EHA 2012

MLN9708 plus LD and MLN9708 plus MP: EHA 2012

Rd vs MEL140 (DSMM XIII)

Pomalidomide + Dex vs Dexamethasone: MM 005

Alternating treatment with different regimens: VMP and RD (PETHEMA/GEM)

Bortezomib + Bendamustine + Prednisone (PETHEMA/GEM)

H. Ludwig 2013

New drugs in clinical evaluation

Agent Mechanism of action

Panobinostat, Vorinostat, Givinostat, Romidepsin

HDAC inhibitor

Perifosine, GSK2110183 Akt inhibitor

Temsirolismus, Everolismus mTOR inhibitor

Selumetinib MEK/ERK inhibitor

Plitidepsin (aplidin)Jun N-terminal Kinase (JNK) activator, anti-angiogenic activity

Dinaciclib CDK inhibitor

MLN8237 Aurora kinase inhibitor

ARRY-520 Kinesin spindle protein (KSP) inhibitor

Elotuzumab anti-CS1

Daratumumab anti-CD38

BHQ880 anti-DKK1

BT062 anti-CD138

Tabalumab Anti-B cell activiating factor (BAFF)

BI-505 Anti-intercellular adhesion molecule 1 (ICAM-1)

H. Ludwig 2013

Assess

- comorbidities

- degree of functional impairment

Select most appropriate drug regimen

Adapt dose if required

Consider the increased risk of infections within

first weeks/months of therapy

Optimize supportive care

-Antibiotics, antivirals, growth factors, anti-thrombotics

Recommendations for clinical practice

H. Ludwig 2013

Thank you for your attention

The future looks bright for elderly myeloma patients

The future looks bright for elderly myeloma patients

H. Ludwig 2013