Post on 17-Mar-2018
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
☐
�
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Type van verstrengeling / financieel belang Naam van commercieel bedrijf
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Ontvangst van honoraria of adviseursfee: Celgene, Johnson and Johnson, Novartis
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Financiële belangen in een bedrijf (aandelen of opties): -
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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.
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%
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.
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
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.
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
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.
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
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.
• 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%
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.
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.
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.
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
• ?