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Update on transplant-ineligible patients: Update on transplant-ineligible patients:

Update on transplant-ineligible patients: - PowerPoint Presentation

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Update on transplant-ineligible patients: - PPT Presentation

Which regimens are best Suzanne Lentzsch MD PhD Columbia University New York Disclosures for Suzanne Lentzsch MD PhD Honoraria Scientific Advisory Board Speakers Bureau No relevant conflicts of interest to declare ID: 431965

mpt patients melphalan survival patients mpt survival melphalan months 2013 treatment pfs maintenance vmp score ash slide response courtesy

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Slide1

Update on transplant-ineligible patients: Which regimens are best?

Suzanne Lentzsch MD, PhDColumbia University, New YorkSlide2

Disclosures for Suzanne Lentzsch, MD, PhD

HonorariaScientific Advisory BoardSpeakers BureauNo relevant conflicts of interest to declare

Major Stockholder

Consultant

No relevant conflicts of interest to declare

Employee

Celgene

Research Support/P.I.

No relevant conflicts of interest to declare

Amgen, Bristol-Myers Squibb,

Celgene

, Janssen,

Millenium

, Onyx

No relevant conflicts of interest to declare

No relevant conflicts of interest to declareSlide3

Treatment Decision in Older Patients

PatientsADLIADLComorbiditiesHospitalizationMedicationsSocial SupportMultiple Myeloma CytogeneticsStage

Tumor burden

Optimal Chemo

Supportive

meds

Goals of Care (CR

vs

Disease Control?)

Expectations

Understanding

Life ExpectancySlide4

Treatment Decision in Transplant I

neligible Patients Frailty ???Melphalan based regimens ???Doublets ???Triplets ???Maintenance ??? Slide5

Frailty score

VariableHR (CI 95%)

P

SCORE

AGE

Age <75 years

1

-

0

Age 75-80 years

1.37 (0.93-2.03)

0.114

1

Age >80 years

2.75 (1.81-4.18)

<0.001

2

CHARLSON INDEX

Charlson

<

1

1

-

0

Charlson

>

2

1.6 (1.07-2.39)

0.021

1

ADL SCORE

ADL >4

1

-

0

ADL

<

4

1.76 (1.14-2.71)

0.01

1

IADL SCORE

IADL >5

1

-

0

IADL

<51.53 (1.03-2.27)0.0361

ADDITIVE TOTAL SCOREPATIENT STATUS0FIT1UNFIT>2FRAIL

Slide courtesy of Palumbo, ASH 2013Slide6

Patients (%)

Overall

Survival

Multivariate Analysis

Lower

risk

Death

FIT

ISS

1-2

FISH

neg

Fit vs. Unfit vs.

Frail

Fit

defined as: score=0 Unfit defined as: score=1 Frail defined as: score

>

2

1-yr OS

Fit

96%

Unfit

93%

Frail

78%

Unfit

vs

Fit

Frail

vs

Fit

ISS 3 vs ISS 1-2

HR vs SR

Fish

ECOG 2-3 vs 0-1

1.24

(0.74,

2.08)

3.11

(1.97,

4.90)

1.77

(1.23,

2.54)1.83 (1.26, 2.63)1.19 (0.81, 1.76)Higher risk DeathFRAIL ISS 3FISH pos

Unfit vs Fit, HR=1.61 p=0.042Frail vs Fit, HR=3.57 p<0.001Slide courtesy of Palumbo, ASH 2013Slide7

Slide courtesy of Palumbo, ASH 2013Slide8

PATIENT STATUS ASSESSMENT

Age (score 0 – 1 – 2) Charlson (score 0 – 1)

ADL (score 0 – 1) IADL (score 0 – 1)

FIT

UNFIT

FRAIL

Additive total score = 0

Additive total score = 1

Additive total score

≥ 2

GO-GO

MODERATE-GO

SLOW-GO

Full-dose

Reduced-dose

Further reduced dose

Dose level 0

Dose level -1

Dose level -2

Lenalidomide

25 mg/d

15 mg/d

10 mg/d

Bortezomib

1.3 mg/m

2

/wk

1.0 mg/m

2

/wk

1.3 mg/m

2

/2wk

Dexamethasone

40 mg/wk

20 mg/wk

10 mg/wk

Cyclophosphamide

300 mg/m

2

d 1,8,15

50 mg/d

50 mg/

qod

T

reatment

algorithm for elderly MM

Slide courtesy of Palumbo, ASH 2013Slide9

Unanswered Question for Transplant Ineligible Patients

Frailty-Adjust Treatment IntensityMelphalan ???Doublets ???Triplets ???Maintenance ??? Slide10

MP better

MPT betterProgression-free survivalMPT betterMP betterOverall survival

NOTE: weights are from random effects analysis

Overall

(I-squared = 61.7%,

p = 0.023)

FR < 75

NMSG

HOVON

Italy

Fr

≥ 75

Turkey

Study

0.67 (0.55– 0.80)

0.50 (0.39– 0.65)

0.89 (0.70–1.13)

0.79 (0.62–1.00)

0.62 (0.48–0.80)

0.61 (0.46–0.82)

0.59 (0.35–0.99)

HR (95% CI)

HR (95% CI)

1

0.5

0.75

1.5

NOTE: weights are from random effects analysis

Overall

(I-squared = 60.6%,

p = 0.026)

NMSG

Study

Italy

FR < 75

HOVON

Fr

≥ 75

Turkey

0.82 (0.66–1.02)

1.12 (0.85–1.47)

HR (95% CI)

1.04 (0.75–1.44)

0.61 (0.45– 0.81)

0.75 (0.57–1.00)0.68 (0.48– 0.96)0.87 (0.46–1.67)HR (95% CI)

10.50.75

1.5

Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials

Fayers

P M et al. Blood 2011;118:1239-1247Slide11

MPT

MPmOS39.3

m

32.7 m

mPFS

20.3 m

14.9 m

Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials

Fayers

P M et al. Blood 2011;118:1239-1247Slide12

Overall survival

in

patients

randomized to

bortezomib

-

melphalan

-prednisone (VMP) or

melphalan

-prednisone (MP) after a median follow-up of 5

years

San Miguel J F et al. JCO 2013;31:448-455Slide13

Wildes

T M et al. JCO 2014;32:2531-2540

Abbreviations: MM, multiple myeloma; MP,

melphalan

and prednisone; MPR,

melphalan

, prednisone, and

lenalidomide

; MPR-R,

melphalan

, prednisone, and

lenalidomide

with

lenalidomide

maintenance; MPT, melphalan, prednisone, and thalidomide; MPV, melphalan, prednisone, and bortezomib

; NR, not reported; OS, overall survival; PFS, progression-free survival; Rd, lenalidomide and low-dose dexamethasone; RD, lenalidomide and high-dose dexamethasone. ↵* Discontinuation rate because of toxicity, specifically during induction where applicable. Global (ie, “any” or “

nonhematologic”) toxicity incidence not reported. ↵† Statistically significant for MPR-R v MP and MPR-R v MPR only.

Initial Therapy in Older Adults With MM: Randomized Trials of MP With or Without the Addition of Novel AgentsSlide14

Unanswered Question for Transplant Ineligible Patients

Frailty – Adjust Treatment IntensityMelphalan or Novel Drugs ???Doublets or Triplets ???Maintenance ??? Slide15

Efficacy and Safety of Three

Bortezomib-Based Induction and Maintenance Regimens in Previously Untreated, Transplant-Ineligible Multiple Myeloma Patients: Final Results from the Randomized, Phase 3b, US Community-Based UPFRONT Study

Slide Courtesy

Niesvizky

,

R

;

ASH 2013Slide16

RESULTSPatients502 patients were randomized to

VD (n=168), VTD (n=167), VMP (n=167)Baseline characteristics were well balanced across the treatment armsMedian age was 73 years (range 38–91)48% of patients had comorbidities at baselineThe most common were diabetes mellitus (21%), renal disease (15%), and chronic pulmonary disease (8%)Slide Courtesy Niesvizky, R; ASH 2013Slide17

Response* ORRs after 13 cycles were 73% (VD), 80% (VTD), and 70% (VMP) including:

30%, 40%, and 32% CR/nCR, respectively37%, 51%, and 41% ≥VGPR, respectively*Response-evaluable population (n=425 patients who received at least one dose of study drug, had measurable disease at baseline, and had at least one post-baseline M-protein measurement)Best confirmed response after 8 (induction) and 13 (induction + maintenance) cycles Slide Courtesy Niesvizky, R; ASH 2013Slide18

PFS (intent-to-treat population) After a median follow-up of 42.7 months, 265 (53%) patients had progressed and/or died

Median PFS (95% CI) was 14.7 months (12.0, 18.6), 15.4 months (12.6, 24.2), and 17.3 months (14.8, 20.3), for VD, VTD, and VMP, respectively, with no global difference among arms (p=0.458)Slide Courtesy Niesvizky, R; ASH 2013Slide19

OS (intent-to-treat population)Median OS (95% CI) was 49.8 months (35.7, not estimable [NE]),

51.5 months (38.5, NE), and 53.1 months (41.1, NE) for VD, VTD, and VMP, respectively, with no global difference among arms (p=0.789)Slide Courtesy Niesvizky, R;

ASH 2013Slide20

UPFRONT TRIAL CONCLUSIONSAfter ~3.5 years’ follow-up, no significant differences in PFS or OS were seen among arms

VTD had the highest toxicity rates and the lowest mean bortezomib dose intensity among the armsVD doublet therapy may be as effective as VTD or VMP triplet therapy in elderly pat (due less toxicity with higher bortezomib intensity?)In accordance with: Recent analysis of VMP data from VISTA suggests that a higher cumulative bortezomib dose, reflecting prolonged treatment duration and/or dose intensity, is associated with superior OS (Mateos MV, et al. ASH 2013, abstract #2155)Slide Courtesy Niesvizky, R; ASH 2013Slide21

Unanswered Question for Transplant Ineligible P

atients Frailty – Adjust Treatment IntensityMelphalan or Novel Drugs!Doublets! or Triplets Maintenance ??? Slide22

Facon T, et al. Blood. 2013;122:abstract 2.

RANDOMIZATION 1:1:1

Arm B

Rd18

Arm C

MPT

LEN + Lo-DEX: 18 Cycles (72 wks)

LENALIDOMIDE 25mg D1-21/28

Lo-DEX 40mg D1,8,15 & 22/28

MEL + PRED + THAL 12 Cycles

1

(72 wks)

MELPHALAN 0.25mg/kg D1-4/42

PREDNISONE 2mg/kg D1-4/42

THALIDOMIDE 200mg D1-42/42

PD, OS and

Subsequent anti-MM Tx

PD or Unacceptable Toxicity

Active Treatment + PFS Follow-up Phase

Screening

LT Follow-Up

Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL

2

(100 mg D1-42/42); MEL

2

0.2 mg/kg D1–4

Stratification: age, country and ISS stage

1

Facon T, et al. Lancet

 2007;370:1209-18

;

2

Hulin C, et al. JCO.

 2009;27:3664-70.

FIRST Trial: Study Design

LEN + Lo-DEX Continuously

LENALIDOMIDE 25mg D1-21/28

Lo-DEX 40mg D1,8,15 & 22/28

Arm A

Continuous Rd

ISS,

International Staging System; LT, long-term; PD, progressive disease; OS, overall survival

Benboubker

L et al. N

Engl

J Med 2014;371:906-917.Slide23

mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, lenalidomide plus low-dose dexamethasone.

Median PFSRd (n=535)

25.5 mos

Rd18 (n=541)

20.7 mos

MPT (n=547)

21.2 mos

Rd

535

400

319

265

218

168

105

55

19

2

0

Rd18

541

391

319

265

167

108

56

30

7

2

0

MPT

547

380

304

244

170

116

58

28

6

1

0

Hazard ratio

Rd vs. MPT: 0.72;

P

= 0.00006

Rd vs. Rd18: 0.70; P = 0.00001 Rd18 vs. MPT: 1.03; P = 0.70349

Time (months)

Patients (%)

100

80

60

40

20

0

0

6

12

18

24

30

36

42

48

54

60

72 wks

FIRST Trial: Final Progression-free Survival

28% reduced risk of disease progression

Benboubker

L et al. N

Engl

J Med 2014;371:906-917.Slide24

FIRST Trial: Overall Survival Interim Analysis

Patients (%)RdRd18MPT535541547

488

505

484

457

465

448

433

425

418

403

393

375

338

324

312

224

209

205

121

124

106

43

44

30

5

6

3

0

0

0

4-year OS

Rd (n= 535)

59%

Rd18 (n= 541)

56%

MPT (n= 547)

51%

Overall survival (months)

100

80

60

40

20

0

0

6

12

18

24

30

36

42

48

54

60

Hazard ratio

Rd vs. MPT: 0.78;

P

=

0.02

Rd vs. Rd18: 0.90;

P

=

0.31

Rd18 vs. MPT: 0.88;

P

=

0.18

Benboubker

L et al. N

Engl

J Med 2014;371:906-917.

574 deaths (35% of ITT)Slide25

Response

a (%)Continuous Rd (n=535)Rd18

(n=541)

MPT

(n=547)

ORR (

≥ PR)

b

75

73

62

CR

15

14

9

VGPR

28

28

19

PR

32

31

34

SD

19

21

27

VGPR or better

43

42

28

Time to response (median,

mos

)

1.8

1.8

2.8

Duration of response (median,

mos

)

35.0

22.1

22.3

FIRST Trial: Response Endpoints

a

IMWG

Criteria; CR, complete response; mos, months ORR, overall response rate; PR, partial response; SD, stable disease; VGPR, very good PR. bResponse assessment for Rd obtained every 4 wks and for MPT every 6 wks; Response and progression rate based on IRAC assessment. Benboubker L et al. N Engl J Med 2014;371:906-917.Slide26

FIRST Trial: ConclusionsContinuous Rd significantly extended PFS

and OS vs. MPTPFS: HR= 0.72 (P= 0.00006)Consistent benefit across most subgroupsRd better than Rd18 (HR= 0.70, P= 0.00001)3 yr PFS: 42% Rd vs 23% Rd18 and MPTPlanned interim OS: HR= 0.78 (P= 0.0168)Rd was superior to MPT across all other efficacy secondary endpointsSafety profile with continuous Rd was manageable Hematological and non-hematological AEs were as expected for Rd and MPTIncidence of hematological SPM was lower with continuous Rd vs. MPTIn NDMM transplant-ineligible patients, the FIRST Trial establishes continuous Rd as a new standard of care

Benboubker

L et al. N

Engl

J Med 2014;371:906-917.Slide27

Unanswered Question for Transplant Ineligible Patients

Frailty – Adjust Treatment IntensityMelphalan or Novel Drugs !!Doublets or Triplets !!Maintenance !! Slide28

Palumbo A et al. JCO 2014;32:634-640

Bortezomib

-

Melphalan

-Prednisone Followed by Maintenance With

Bortezomib

-Thalidomide (VMP-VT) Compared With

Bortezomib

-

Melphalan

-Prednisone (VMP) for Initial Treatment of Multiple Myeloma

N=511Slide29

Survival outcomes in the intention-to-treat population, according to study group.

PFS

OS

TNT

OS after Relapse

Palumbo A et al. JCO 2014;32:634-640Slide30

VMP vs. VMPT-VT: 3-year PFS: 41

% vs 56% median PFS: 24.8 vs 35.3 months (P .001)TNT 27.8 vs 46.6 months (P .001)5-year overall survival (OS) was greater with VMPT-VT (61%) than with VMP (51%; HR, 0.70; P .01). VMPT-VT group, more grade 3 to 4 adverse events including neutropenia (38%), thrombocytopenia (22%), peripheral neuropathy (11%), and cardiologic events (11%). ConclusionBortezomib and thalidomide maintenance significantly improved OS in multiple myeloma patientsVT-Maintenance for Non-Transplant Patients

Palumbo A et al. JCO 2014;32:634-640Slide31

UnAnswered Question for Transplant Ineligible Patients?

Frailty Adjust Treatment IntensityDetermine the goals of care !!Melphalan or Novel Drugs !!Doublets or Triplets !!Less toxic treatment allows longer treatment

Maintenance !! Slide32

32

Thank You !!