Niels van de Donk Afdeling Hematologie, · PDF fileNiels van de Donk Afdeling Hematologie,...

Maintenance in Multiple Myeloma: YES

Niels van de Donk

Afdeling Hematologie, UMCU

BelangenverklaringIn overeenstemming met de regels van de Inspectie van de Gezondheidszorg (IGZ)

Naam: Niels van de Donk

Organisatie: UMCU

☐

�

Ik heb geen 'potentiële' belangenverstrengeling

Ik heb de volgende mogelijke belangenverstrengelingen:�

Type van verstrengeling / financieel belang Naam van commercieel bedrijf

Ontvangst van subsidie(s)/research ondersteuning: Celgene, Johnson and Johnson, Onyx, Genmab

Ontvangst van honoraria of adviseursfee: Celgene, Johnson and Johnson, Novartis

Lid van een commercieel gesponsord ‘speakersbureau’: -

Financiële belangen in een bedrijf (aandelen of opties): -

Andere ondersteuning (gelieve te specificeren): -

Wetenschappelijke adviesraad: -

Ik heb de volgende mogelijke belangenverstrengelingen:

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Maintenance; Onderhoud

Maintenance until progression !

HOVON-126: Ixazomib-thalidomide-dexamethason

9Td

Ixazomib 1x/week oraalThalidomide 100 mg/dag

Dexamethason 40 mg/week9 cycli per 4 weken

Ixazomib tot aan progressie

Placebo tot aan progressie

Maintenance therapy

• Majority of MM patients relapse

• Maintenance therapy may control the proliferation of residual malignant cells

� prolong duration of response and ultimately � prolong duration of response and ultimately prolong survival

– Chemotherapy: no survival benefit

– Interferon: minimal to no survival benefit, not well tolerated

– Corticosteroids: inconsistent benefit

– Thalidomide: improved PFS and to lesser degree improved OS, worse QoL (except for sleep), severe neuropathy leading to discontinuation (adverse FISH: no benefit on PFS, impaired OS)

Ludwig Blood 2012

Lenalidomide

• Oral drug

• Better tolerated

� Considered a suitable candidate for use as

maintenance therapymaintenance therapy

• Conflicting results have emerged from trials

evaluating lenalidomide maintenance therapy

Ludwig Blood 2012

Study Setting Comparison N Consolidation Len maintenance

IFM-05-02 Post auto-SCT Placebo 614 Len 25 mg on

days 1-21 of

28 day cycle x2

10 mg daily x 3 months, increased

to 15 mg daily if tolerated, until

progression

CALGB 100104# Post auto-SCT Placebo 460 No 10 mg daily (up to 15 mg daily),

until progression

MM-015 Post MPR Placebo 459 No 10 mg daily d-21 of 28d cyckle until

induction in non-

transplant eligible

patients

progression or unacceptable

toxicity

RV-MM-PI209 2x2 design

comprising of

both auto-SCT

and non-

transplant arm

No

maintenance

402 No 10 mg daily d-21 of 28d cycle until

progression or unacceptable

toxicity

# Allowed cross-over after study unblinding

Palumbo NEJM 2012; McCarthy NEJM 2012; Attal NEJM 2012; Boccadoro ASCO 2013

*Jan 2011: LEN maintenance stopped in all patients (SPM)

Progression-free survival

• Median PFS in IFM (Nov 2013): 46 versus 24 months; Δ22 months

• Median TTP in CALGB (Jan 2013): 50 versus 27 months ; Δ23 months

• Median PFS in MM-015 (NEJM): 31 vs 14 vs 13 months ; Δ18 months

• Median PFS in RV-MM-P1209: 37 vs 26 months; Δ11 months

�PFS advantage independent of quality of response (also in CR),

beta-2 microglobulin, and del(13q)

Palumbo NEJM 2012; McCarthy NEJM 2012; Attal NEJM 2012; Boccadoro ASCO 2013

MetaMeta--Analysis: ResultsAnalysis: Results

Study name HRLower limit

Upper limit p-Value

IFM 05-02 0.500 0.410 0.610 <0.001

CALGB 100104 0.480 0.363 0.635 <0.001

MM-015 0.340 0.179 0.645 <0.001

RV-MM-P1209 0.520 0.402 0.673 <0.001

SUMMARY ESTIMATE 0.491 0.425 0.560 <0.001

Lenalidomide maintenance and PFS

SUMMARY ESTIMATE 0.491 0.425 0.560 <0.001

Lenalidomide maintenance and OS

HR for death or progression; LEN vs. no maintenance. Cochran Q = 1.51, p = 0.68, I2 = 0%

Singh P, et al. Lenalidomide Maintenance Therapy in Multiple Myeloma: a Meta-Analysis of Randomized Trials. Oral presentation at the 55th Annual Meeting of American Society of Hematology (ASH) . 2013; December 7-10; New Orleans, LA.


Overall survival

• Increasing use of novel agents in salvage

regimens

�Survival advantage difficult to demonstrate

�Requires large numbers of patients �Requires large numbers of patients

• Significant OS advantage of LEN maintenance

in 2 out of 4 studies

PFS2, second PFS

• In view of significant improvement of PFS with

comparable OS rates, there may be a concern

– Whether the continuous administration of LEN may

impact the efficacy of treatment at relapseimpact the efficacy of treatment at relapse

• European Medicines Agency (EMA) recommends to

use progression-free survival 2 (PFS2) to answer this

question

• PFS2 is defined as time from randomization to:

� Time of objective disease progression after next-line Tx, or

� Death from any cause, or

� Start of 3rd line (surrogate of PD on 2nd line)

• PFS2 is based on ITT population

PFS2 Definition as per EMAPFS2 Definition as per EMA

�

• PFS2 is based on ITT population

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/01/WC500137128.pdf.

PFS2

Randomization

Next-line of treatmentProtocol treatment

Disease progression

2nd Disease progression

PFS

Dimopoulos MA et al. PFS2 in Elderly Patients With Newly Diagnosed Multiple Myeloma: Results From the MM-015 Study. Oral presentation at the 55th Annual Meeting of the American Society of Hematology (ASH). 2013; December 7-10; New Orleans, LA, USA

Pts whoStarted2nd Line

Median: 31 mos Median: 13 mos

MPR-R (n=152) MP (n=154)1st Line Tx

PFS

2nd Line Tx

MMMM--015: PFS and PFS2015: PFS and PFS2

Pts whoStarted2nd Line

Tx(n=129)

2nd Line Tx

(n=85)

N=152 Median: 39.7 mos N=154 Median: 28.8 mosPFS2

Deathsbefore2nd line

n=5

No PDn=62

Deathsbefore2nd line

n=5No PDn=20

Dimopoulos MA et al. PFS2 in Elderly Patients With Newly Diagnosed Multiple Myeloma: Results From the MM-015 Study. Oral presentation at the 55th Annual Meeting of the American Society of Hematology (ASH). 2013; December 7-10; New Orleans, LA, USA

IFM 2005-02 : PFS 2

P=0.0750

60

70

80

90

100

Patients

(%

)

Lenalidomide

Placebo

0

10

20

30

40

Patients

(%

)

307 268 233 192 163 107 25Placebo307 273 237 202 168 118 40Lenalidomide

N at risk

0 12 24 36 48 60 72

Months of follow-up

Overall survival

• Increasing use of novel agents in salvage

regimens

�Survival advantage difficult to demonstrate

�Requires large numbers of patients �Requires large numbers of patients

• Meta-analysis: Four randomized controlled

trials

Meta-analysis

MetaMeta--Analysis: ResultsAnalysis: Results

Study name HRLower limit

Upper limit p-Value

IFM 05-02 1.060 0.820 1.375 0.664

CALGB 100104 0.610 0.424 0.878 0.008

Lenalidomide maintenance and OS

MM-015 0.790 0.528 1.181 0.251

RV-MM-P1209 0.620 0.417 0.923 0.018

SUMMARY ESTIMATE 0.767 0.574 1.023 0.071

HR for death; LEN vs. no maintenance. Cochran Q = 8.11, p = 0.044, I2 = 63%


Palumbo, Torino, Italy

First study

• FIRST study not (yet) included in meta-analysis, but will be added in the final analysis

RA

ND

OM

IZA

TIO

N 1

:1:1

Arm BRd18

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

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

FIRST Trial: Study Design

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

Arm AContinuous Rd

RA

ND

OM

IZA

TIO

N 1

:1:1

Arm CMPT

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

PD

or

Un

acce

pta

ble

To

xici

ty

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.

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

Facon T, et al. Continuous Lenalidomide and Low-dose Dexamethasone Demonstrates a Significant PFS and OS Advantage in Transplant Ineligible NDMM Patients – The FIRST Trial: MM-020/IFM 0701. Plenary presentation at: American Society of Hematology. 2013; December 7-10; New Orleans, LA.

Median PFS

Rd (n=535) 25.5 mos

Rd18 (n=541) 20.7 mos

MPT (n=547) 21.2 mos

Hazard ratioRd vs. MPT: 0.72; P = 0.00006Rd vs. Rd18: 0.70; P = 0.00001 Rd18 vs. MPT: 1.03; P = 0.70349

Pat

ien

ts (%

)100

80

60

FIRST Trial: Final ProgressionFIRST Trial: Final Progression--free Survivalfree Survival

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

Time (months)

Pat

ien

ts (%

)

40

20

00 6 12 18 24 30 36 42 48 54 60

72 w

ks


FIRST Trial: Overall Survival Interim AnalysisFIRST Trial: Overall Survival Interim Analysis574 deaths (35% of ITT)574 deaths (35% of ITT)

Pat

ien

ts (

%)

4-year OS

Rd (n= 535) 59.4%

Rd18 (n= 541) 55.7%

MPT (n= 547) 51.4%

100

80

60

40Pat

ien

ts (

%)

RdRd18MPT

535541547

488505484

457465448

433425418

403393375

338324312

224209205

121124106

434430

563

000

Overall survival (months)

40

20

00 6 12 18 24 30 36 42 48 54 60

Hazard ratioRd vs. MPT: 0.78; P = 0.0168Rd vs. Rd18: 0.90; P = 0.307Rd18 vs. MPT: 0.88; P = 0.184


Conclusions 1

• Clinical benefit in terms of PFS and OS

� Safety?

MetaMeta--Analysis: Grade 3Analysis: Grade 3--4 Adverse Events 4 Adverse Events During Lenalidomide MaintenanceDuring Lenalidomide Maintenance

• Lenalidomide maintenance is associated with increased risk of grade 3-4 adverse events

• Neutropenia: OR 4.9, p < 0.001

• Thrombocytopenia: OR 2.7, p < 0.001


• Thrombocytopenia: OR 2.7, p < 0.001

• Fatigue: OR 2.3, p = 0.01

• Venous thromboembolism: OR 3.2, p = 0.02

Palumbo ASCO 2013

MetaMeta--Analysis: Results Analysis: Results

Study name

Odds ratio

Lower limit

Upper limit p-Value

IFM 05-02 1.64 0.99 2.72 0.053

CALGB 100104 2.05 1.07 3.93 0.031

MM-015 1.43 0.61 3.34 0.412

RV-MM-P1209 0.85 0.26 2.85 0.798

Second Primary Malignancies

RV-MM-P1209 0.85 0.26 2.85 0.798

SUMMARY ESTIMATE 1.62 1.15 2.29 0.006

Odds of developing SPM;LEN vs. placebo/no maintenance Cochran Q = 1.67, p = 0.644, I2 = 0%


FIRST Trial: Second Primary Malignancy FIRST Trial: Second Primary Malignancy

Continuous Rd (n=532)

Rd 18(n=540)

MPT(n=541)

Hematological malignancies, n (%) 2 (0.4) 2 (0.4) 12 (2.2)

AML 1 (0.2) 1 (0.2) 4 (0.7)

MDS 1 (0.2) 1 (0.2) 6 (1.1)

MDS to AML 0 (0.0) 0 (0.0) 2 (0.4)

B-cell 0 (0.0) 0 (0.0) 0 (0.0)

Solid tumors, n (%) 15 (2.8) 29 (5.4) 15 (2.8)

Invasive SPM, n (%) 17 (3.2) 30 (5.6) 27 (5.0)

Patients with ≥ 1 NMSC (non-invasive), n (%)

22 (4.1) 17 (3.1) 21 (3.9)

Total patients with SPM, n (%) 37 (7.0) 44 (8.1) 47 (8.7)

AML, acute myeloid leukemia; MDS, myelodysplastic syndromes; MPT, melphalan, prednisolone, thalidomide; NMSC; nonmelanoma skin cancer; Rd, lenalidomide plus low-dose dexamethasone; SPM, second primary malignancy.


QoL

• QoL data not uniformly reported in most

studies

MM-015: QoL

• Health-Related QoL was secondary end-point in MM-015 study

– ≥VGPR� improved QoL

– Progressive disease� impaired QoL– Progressive disease� impaired QoL

• “Clinically meaningful improvements in health-related QoL more common in MPR-R group than MPR or MP groups”

Dimopoulos Haematologica 2013; Dimopoulos Leuk Lymph 2013

Conclusions

• Major PFS benefit in meta-analysis

– LEN (Hazard ratio: 0.49)

• (trend towards) OS benefit in meta-analysis

– LEN (Hazard ratio: 0.77) ↑HR-QoL#

# examined in one study

(MM-015)

• Increase in side effects / SPMs↑

(SPMs ↑ not in FIRST study)

↑HR-QoL

Physicians and patients must weigh the risks and

benefits of LEN maintenance therapy

Sonneveld, JCO 2012; Palumbo JCO 2010

BORT maintenance

• Especially high-risk patients seem to benefit

from bortezomib

– Hovon-65/GMMG-HD4 study: long-term

bortezomib administration during induction and bortezomib administration during induction and

maintenance, overcomes part of the adverse

impact of del(17p)

Sonneveld JCO 2012; Neben Blood 2012

HOVON-65

Sonneveld JCO 2012; Neben Blood 2012

BORT maintenance

• Especially high-risk patients seem to benefit from bortezomib

– Hovon-65/GMMG-HD4 study: long-term bortezomib administration during induction and maintenance, overcomes part of the adverse impact of del(17p) overcomes part of the adverse impact of del(17p)

– TT3: Incorporation of bortezomib abrogated the negative prognostic impact of del(17p) in patients with low-risk disease as defined by GEP

�importance of the cumulative dose of bortezomib administered.

Sonneveld JCO 2012; Neben Blood 2012; Shaughnessy BJH 2009

-Major clinical benefit

-Good QoL

-Opname ziekenhuis

-Poor QoL

-Veel kosten voor relatief

beperkte

overlevingswinst

Maintenance

• Clinical relevance of maintenance

• Refinement

Maintenance

• Subset of patients benefitting the most from LEN maintenance is not yet defined– High-risk

– Low-risk

– Cytogenetics

• Duration of maintenance?• Duration of maintenance?– Until progression

– Fixed duration (2 years)

• Stop– Immunologic CR

– Molecular CR

� MRD assessment in future trials to assess the efficacy / guide maintenance/consolidation strategies

Maintenance

• ?

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