update on transplant-ineligible patients: which regimens are best?

Update on transplant-ineligible patients: 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 declareMajor Stockholder

Consultant

No relevant conflicts of interest to declareEmployee

CelgeneResearch Support/P.I.

No relevant conflicts of interest to declare

Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millenium, Onyx



Treatment Decision in Older Patients

Patients• ADL• IADL• Comorbidities• Hospitalization• Medications• Social Support

Multiple Myeloma • Cytogenetics• Stage• Tumor burden• Optimal Chemo• Supportive meds

Goals of Care (CR vs Disease Control?) ExpectationsUnderstandingLife Expectancy

Treatment Decision in Transplant Ineligible Patients

• Frailty ???

• Melphalan based regimens ???

• Doublets ???

• Triplets ???

• Maintenance ???

Frailty score

Variable HR (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<5 1.53 (1.03-2.27) 0.036 1

ADDITIVE TOTAL SCORE PATIENT STATUS

0 FIT

1 UNFIT

>2 FRAIL Slide courtesy of Palumbo, ASH 2013

Pat

ien

ts (

%)

Overall Survival Multivariate Analysis

Lower risk DeathFIT

ISS 1-2FISH 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 3

FISH pos

Unfit vs Fit, HR=1.61 p=0.042

Frail vs Fit, HR=3.57 p<0.001

Slide courtesy of Palumbo, ASH 2013

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/m2/wk 1.0 mg/m2/wk 1.3 mg/m2/2wk

Dexamethasone 40 mg/wk 20 mg/wk 10 mg/wk

Cyclophosphamide 300 mg/m2 d 1,8,15 50 mg/d 50 mg/qod

Treatment algorithm for elderly MM


Unanswered Question for Transplant Ineligible Patients

• Frailty-Adjust Treatment Intensity

• Melphalan ???

• Doublets ???

• Triplets ???

• Maintenance ???

MP betterMPT better

Progression-free survival

MPT better MP better

Overall 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)

10.5 0.75 1.5

NOTE: weights are from random effects analysis

Overall (I-squared = 60.6%, p = 0.026)

NMSG

Study

Italy

FR < 75

HOVONFr ≥ 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)

10.5 0.75 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;118:1239-1247

MPT MP

mOS 39.3 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;118:1239-1247

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;31:448-455

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 Agents


• Frailty – Adjust Treatment Intensity

• Melphalan or Novel Drugs ???

• Doublets or Triplets ???

• Maintenance ???

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 2013

RESULTSPatients

• 502 patients were randomized to – VD (n=168),

– VTD (n=167),

– VMP (n=167)

• Baseline characteristics were well balanced across the treatment arms

– Median age was 73 years (range 38–91)

– 48% of patients had comorbidities at baseline

• The most common were diabetes mellitus (21%), renal disease (15%), and chronic pulmonary disease (8%)


Response*

• ORRs after 13 cycles were 73% (VD), 80% (VTD), and 70% (VMP) including:– 30%, 40%, and 32% CR/nCR, respectively– 37%, 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


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)


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)


UPFRONT TRIAL CONCLUSIONS

• After ~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 arms

• VD 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)




• Melphalan or Novel Drugs!

• Doublets! or Triplets

• Maintenance ???

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

RA

ND

OM

IZA

TIO

N 1

:1:1

Arm BRd18

Arm CMPT

LEN + Lo-DEX: 18 Cycles (72 wks) LENALIDOMIDE 25mg D1-21/28Lo-DEX 40mg D1,8,15 & 22/28

MEL + PRED + THAL 12 Cycles1 (72 wks)MELPHALAN 0.25mg/kg D1-4/42PREDNISONE 2mg/kg D1-4/42THALIDOMIDE 200mg D1-42/42

PD

, OS

an

d

Su

bse

qu

ent

anti

-MM

Tx

PD

or

Un

acce

pta

ble

To

xici

ty

Active Treatment + PFS Follow-up PhaseScreening LT Follow-Up

Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL2 (100 mg D1-42/42); MEL2 0.2 mg/kg D1–4

• Stratification: age, country and ISS stage

1Facon T, et al. Lancet 2007;370:1209-18; 2Hulin C, et al. JCO. 2009;27:3664-70.

FIRST Trial: Study Design

LEN + Lo-DEX ContinuouslyLENALIDOMIDE 25mg D1-21/28Lo-DEX 40mg D1,8,15 & 22/28

Arm AContinuous 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.

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

Median PFS

Rd (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)

Pat

ien

ts (

%)

100

80

60

40

20

00 6 12 18 24 30 36 42 48 54 60

72 w

ks

FIRST Trial: Final Progression-free Survival

28% reduced risk of disease progression


FIRST Trial: Overall Survival Interim AnalysisP

atie

nts

(%

)

RdRd18MPT

535541547

488505484

457465448

433425418

403393375

338324312

224209205

121124106

434430

563

000

4-year OS

Rd (n= 535)

59%

Rd18 (n= 541)

56%

MPT (n= 547)

51%

Overall survival (months)

100

80

60

40

20

00 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


574 deaths (35% of ITT)

Responsea (%)

Continuous Rd

(n=535)Rd18

(n=541)MPT

(n=547)

ORR (≥ PR)b75 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

aIMWG 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.


FIRST Trial: Conclusions

• Continuous Rd significantly extended PFS and OS vs. MPT– PFS:

• HR= 0.72 (P= 0.00006)• Consistent benefit across most subgroups• Rd better than Rd18 (HR= 0.70, P= 0.00001)• 3 yr PFS: 42% Rd vs 23% Rd18 and MPT

– Planned interim OS: HR= 0.78 (P= 0.0168)– Rd was superior to MPT across all other efficacy secondary endpoints

• Safety profile with continuous Rd was manageable – Hematological and non-hematological AEs were as expected for Rd and

MPT– Incidence of hematological SPM was lower with continuous Rd vs. MPT

• In NDMM transplant-ineligible patients, the FIRST Trial establishes continuous Rd as a new standard of care




• Melphalan or Novel Drugs !!

• Doublets or Triplets !!

• Maintenance !!

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=511

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

PFS

OS

TNT

OS after Relapse


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 patients

VT-Maintenance for Non-Transplant Patients


UnAnswered Question for Transplant Ineligible Patients?

• Frailty – Adjust Treatment Intensity– Determine the goals of care !!

• Melphalan or Novel Drugs !!

• Doublets or Triplets !!– Less toxic treatment allows longer treatment

• Maintenance !!

32

Thank You !!

update on transplant-ineligible patients: which regimens are best?

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