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Hablemos de mantenimiento:
posTMO: La conjetura de la
cronología
Javier de la RubiaHospital Doctor Peset, Valencia
Adaptado de Kurtin et al. Clin J Oncol Nurs. 2013; 17 Suppl:7-11
Multiple myeloma. Clinical evolution
ATSP vs. QTc
Estudio
IFM90 (NEJM 96)
MRC7 (NEJM 03)
MMSG It. (Blood 04)
MAG91 (ASH 99)
PETHEMA (Blood 05)
US Interg. (JCO 06)
Nº casos
200
401
194
190
164
516
Edad
≤65
≤65
50-70
55-65
<65
<70
RC (%)
5 vs. 22
8 vs. 44
6 vs. 25
-
11 vs. 30
11 vs. 11
Mediana SLE
18 vs. 28
19 vs. 31
16 vs. 28
19 vs. 25
34 vs. 42
21 vs. 25
Mediana SG
44 vs 57
42 vs. 54
42 vs. 58+
45 vs. 42
67 vs. 65
53 vs. 58
De la Rubia J. 2007
Complete response
• OS is not a realistic end-point
• TTP/PFS while acceptable will take years to complete
• CR is an important goal of therapy and it can be
reliably defined
• CR rates even with new regimens is less than 30-40%
• CR is recommended as an appropriate surrogate end-
point for regulatory purposes
Rajkumar SV 2006
Depth of response
MR
PR
VGPRnCR
CRsCR
Treatment initiation
Progression
Time
Depth of response is related to TTP
Importance of achieving complete
response
0 12 24 36 48 60 72 84 96
Months from diagnosis
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
Cu
mu
lati
ve P
rop
ort
ion
Su
rviv
ing
CR vs nCR or vs. SD CR vs PR nCR vs PR
P= 0.01P< 10-6
P= 0.04
0 12 24 36 48 60 72 84 96
Months from diagnosis
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0C
um
ula
tiv
e P
rop
ort
ion
Ev
en
t F
ree S
urv
ivin
gCR vs nCR or PR or SD nCR vs PR nCR vs SD
P< 10-5
P= 0.07P= 0.7
CR, n= 278 nCR, n=124 PR, n=280 PD, n=25
EFS OS
Lahuerta et al. ASH 2008 (abstract 161), oral presentation
Outcome according to post-transplant response
CR nCR PR SD PD
Medians EEF (months) 61 40 34 44 13
Medians OS (months) NR NR 61 NR 15
Tratamiento futuro de 1ª línea en jóvenes
Diagnóstico
Estratificación según riesgo
(ISS, citogenética convencional, FISH)
Riesgo estándar Alto riesgo
Nuevos esquemas de inducción (EC)
ATSP-1
ATSP-2 si <MBRP
o si recaída >2 años
Nuevos esquemas de inducción (EC)
¿ATSP nuevo acondicionamiento?
¿Alo-TPH (AIRE)?
Mantenimiento
De la Rubia J. 2007
Mantenimiento
The true value of CR relies on the MRD status,
and CR w/o MRD is no better than PR
The true value of CR relies on the MRD status,
and CR w/o MRD is no better than PR
MRD allows for more stringent evaluation and can provide
prognostic information
All levels of MRD are usually associated with
unsustained remissions
1. Martinez-Lopez et al., Blood. 2014;123:30732. Mateos MV. Blood Rev 2015;29:387–403
3. Poon ML. Cancer Therapy 2008;6:275-284.
Adaptado de Poon ML.3
But MRD- today means that we don’t detect myeloma cells
with actual techniques…
there is still undetectable residual disease
1. Martinez-Lopez et al., Blood. 2014;123:30732. Mateos MV. Blood Rev 2015;29:387–403
3. Poon ML. Cancer Therapy 2008;6:275-284.
MRD reappearance during follow-up monitoring
predicts clinical relapses
Patients in CR + flow CRafter up-front
treatment
MRD monitoring during follow-up
MRD reappearance:85% had clinical relapse
MRD reappearance
Ongoing major MRDresponse
MRD persistence
Paiva B, et al. Haematologica. 2014;99 Suppl 1:246-7.Ferrero S, et al. Leukemia. 2015;29:689-95.
• Therapy administered for a prolonged period of
time to maintain the response previously
achieved
• Maintenance therapy must be convenient, be
safe and well-tolerated long-term
• Not prevent the use, or reduce the efficacy, of
other future treatments
Why maintenance?
Treatment for patients with newly diagnosed multiple myeloma in 2015.
Mateos MV, Ocio EM, Paiva B, Rosiñol L, Martínez-López J, Bladé J, Lahuerta JJ, García-Sanz R, San Miguel JF.; Blood Rev. 2015;29:387-403
(Intro section on maintenance)
MRD and “Operational Cure”
CR, complete response; MRD, minimal residual disease; PR, partial response;
sCR, stringent CR; VGPR, very good PR. Mateos MV, et al. Blood Rev 2015;29:387.
Multiple myeloma. Clinical evolution
Adaptado de Kurtin et al. Clin J Oncol Nurs. 2013; 17 Suppl:7-11
Multiple myeloma. Clinical evolution
Adaptado de Kurtin et al. Clin J Oncol Nurs. 2013; 17 Suppl:7-11
It is generally accepted that the PFS and OS benefits for MM patients
mainly arise from first-line therapy. Thus, maintaining the response
achieved after first-line therapy is an important objective because most
patients will eventually experience a relapse and their disease will
progress.
ALCYONE: PFS
• Consistent PFS benefit across subgroups
PF
S (
%)
0
20
40
60
80
0 3 6 9 12 15 18 27
Mos
356
350
303
322
276
312
261
298
231
285
127
179
61
93
0
0
2
10
Pts at Risk, n
VMP
Dara-VMP
21 24
18
35
12-mo PFS 18-mo PFS
HR: 0.50
(95% CI: 0.38-0.65; P < .0001)
VMP
Median PFS: 18.1 mos
Dara-VMP
Median PFS: not reached
87%
72%
76%
50%
100
50% reduction in risk of
progression or death in
Dara-VMP arm
Median f/u: 16.5 mos (range: 0.1-28.1)
Mateos MV, et al. ASH 2017. Abstract LBA-4.
Front-line. Transplant candidates
Dex, dexametasona; Len, lenalidomida; TTP, tiempo hasta progresión.
Los pacientes que recibieron Len + Dex demostraron un incremento estadísticamente significativo en
el TTP comparado con pacientes que recibieron Placebo + Dex (P < .001)1
1. Dimopoulos M, et al. Leukemia. 2009;23:2147-2152.
300 10 20
100
0
25
50
75
TTP (Meses)
Pacie
nte
s (
%)
Placebo + Dex, mediana 4.6 meses
Len + Dex, mediana 13.4 meses
P < .001
El Uso Continuado de Lenalidomida + Dexametasona Aumenta
Significativamente el TTP.
Subanálisis de MM-009/0010
• The recommended starting dose for LEN maintenance therapy is
10 mg once daily given continuously (days 1-28 of 28-day cycles)
until PD or unacceptable toxicity2
– After 3 cycles, the dose can be increased to 15 mg once daily if tolerated
Key studies to support LEN maintenance
CALGB, Cancer and Leukemia Group B; IFM, Intergroupe Francophone Multiple Myelome; LEN, lenalidomide; OS, overall survival; PD, progressive disease.
1. McCarthy PL. N Engl J Med. 2012;366:1770-1781. 2. Revlimid (lenalidomide) [package insert]. Summit, NJ. Celgene Corporation. 2017. 3. Attal M. N Engl J Med.
2012;366:1782-1791.
Analyses supported approval
of LEN Maintenance
IFM
2005-02
Study
unblinding3
Jul 7, 2010
Survival
update3
Oct 1, 2011
Updated
efficacy and
safety2
Mar 1, 2015
Updated OS2
Feb 1, 2016
CALGB
100104
Study
unblinding1
Dec 17,
2009
Survival
update1
Oct 31,
2011
Updated
efficacy and
safety2
Mar 1, 2015
Updated OS2
Feb 1, 2016
2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
CALGB 100104: Study design and endpoints
• Primary endpoint: TTP (time from ASCT to PD/death)
• Secondary endpoints: OS, post-ASCT response, long-term LEN
feasibility
aAll patients received thromboprophylaxis; bLEN dose adjustments between 5-15 mg permitted.
ASCT, autologous stem cell transplant; β2-M, β2-microglobulin; CALGB, Cancer and Leukemia Group B; CR, complete response; LEN, lenalidomide; MEL200, melphalan 200
mg/m2; MR, minimal response; OS, overall survival; PD, progressive disease; PR, partial response; R, randomization; SD, stable disease; THAL, thalidomide; TTP, time to
progression; Tx, treatment.
McCarthy PL. N Engl J Med. 2012;366:1770-1781.
R 1:1CR, PR,
MR, SD
Placebo
(n = 229)
MEL200
ASCT
N = 460
• ≤ 70 years of age
• ≤ 1 yr from start of Tx
• Stratified by β2-M and
THAL and LEN use
during induction
LEN
10 mg/dayb
(n = 231)
MaintenanceaRestaging(Within 100 days)
23
CALGB 100104: Event-Free Survival & SPM
ASCT, autologous stem cell transplant; CALGB, Cancer and Leukemia Group B; EFS, event-free survival; HR, hazard ratio; LEN, lenalidomide; PBO, placebo; PD, progressive
disease; SPM, second primary malignancy.
McCarthy PL. N Engl J Med. 2012;366:1770-1781.
• EFS analysis (time to SPM, PD, or death) demonstrated a positive
benefit-risk profile for LEN maintenance despite higher SPM incidence
– Hematologic SPM: 8 (LEN; 3.5%) vs 1 (PBO; 0.4%)
– Solid-tumor SPM: 10 (LEN; 4.3%) vs 5 (PBO; 2.2%)
Cutoff: Oct 2011
24
CALGB 100104: Overall Survival
• LEN maintenance significantly prolonged OS vs placebo
ASCT, autologous stem cell transplant; CALGB, Cancer and Leukemia Group B; HR, hazard ratio; LEN, lenalidomide; N/A, not applicable; OS, overall survival; PBO, placebo.
McCarthy PL. N Engl J Med. 2012;366:1770-1781.
CALGB 100104: Progression-Free Survival
CALGB, Cancer and Leukemia Group B; HR, hazard ratio; LEN, lenalidomide; PBO, placebo; PFS, progression-free survival.
Revlimid (lenalidomide) [package insert]. Summit, NJ. Celgene Corporation. 2017.
Cut-off: March 1, 2015
PFS, mos
1.0
0.8
0.6
0.4
0.2
0.0
0 12 24 36 48 60 72 84 96 108
Su
rviv
al P
rob
ab
ilit
y
HR (95% CI): 0.38 (0.28, 0.50)
Number of patients at risk:
LEN 231 194 158 121 102 82 40 16 5 0
PBO 229 116 57 29 20 18 11 3 0
Median PFS Events, n (%)
LEN 68.6 mos 97 (42)
PBO 22.5 mos 116 (51)
CALGB 100104: Overall Survival
CALGB, Cancer and Leukemia Group B; HR, hazard ratio; LEN, lenalidomide; NE, not estimable; OS, overall survival.
Revlimid (lenalidomide) [package insert]. Summit, NJ. Celgene Corporation. 2017.
OS at Updated Analysis (1 Feb
2016)
LEN
(n = 231)
Placebo
(n = 229)
OS events, n (%) 82 (35) 114 (50)
Median, mos (95% CI) 111.0 (101.8-NE) 84.2 (71.0-102.7)
HR (95% CI) 0.59 (0.44-0.78)
IFM 2005-02: Study Design and Endpoints
aAs measured by FISH; bConsolidation phase added at first protocol amendment (Sept 2006).
ASCT, autologous stem cell transplant; β 2-M, β2-microglobulin; del: deletion; EFS, event-free survival; FISH, fluorescence in situ hybridization; IFM, Intergroupe Francophone
du Myélome; LEN, lenalidomide; NDMM, newly diagnosed multiple myeloma; OS, overall survival; PFS, progression-free survival; pts, patients; R, randomization; SD, stable
disease; VGPR, very good partial response.
Attal M. N Engl J Med. 2012;366:1782-1791.
LEN 25 mg/day
days 1-21
Placebo
(n = 307)
N = 614
•NDMM; < 65 yrs of age
•≥ SD within 6 mos of
ASCT
•Stratified according to
β2-M (≤ 3 or > 3, del(13),a
≥ VGPR post-ASCT
LEN
10-15 mg daily
(n = 307)
Maintenanceuntil progression
Consolidationb
2 × 28-day cycles
R 1:1
28
IFM 2005-02: Progression-Free Survival
• At the updated data cutoff (median follow-up of 86.0 mos), LEN
maintenance prolonged median PFS vs placebo
HR, hazard ratio; IFM, Intergroupe Francophone du Myélome; LEN, lenalidomide; PBO, placebo; PFS, progression-free survival.
Revlimid (lenalidomide) [package insert]. Summit, NJ. Celgene Corporation. 2017.
Cutoff: March 1, 2015
PFS, mos
1.0
0.8
0.6
0.4
0.2
0.0
0 12 24 36 48 60 72 84 96 108
Su
rviv
al P
rob
ab
ilit
y
HR (95% CI): 0.53 (0.44, 0.64)
Number of patients at risk:
LEN 307 243 208 158 124 105 87 49 5 0
PBO 307 225 140 92 61 47 36 19 1
Median PFS Events, n (%)
LEN 46.3 mos 191 (62)
PBO 23.8 mos 248 (81)
29
IFM 2005-02: Overall Survival
• With a median follow-up of 96.7 mos at a Feb 1, 2016 cutoff,
median OS was 105.9 vs 88.1 mos for LEN vs placebo
HR, hazard ratio; IFM, Intergroupe Francophone du Myélome; LEN, lenalidomide; NE, not estimable; OS, overall survival.
Revlimid (lenalidomide) [package insert]. Summit, NJ. Celgene Corporation. 2017.
OS at Updated Analysis (1 Feb 2016)LEN
(n = 307)
Placebo
(n = 307)
OS events, n (%) 143 (47) 160 (52)
Median, mos (95% CI) 105.9 (88.8-NE) 88.1 (80.7-108.4)
HR (95% CI) 0.90 (0.72-1.13)
Myeloma XI: LEN Mantenimiento en MMND
Diseño Estudio
• Endpoint primario: SLP y SG
• N = 1551 (Elegibles = 828; No elegibles = 723)
• Mediana seguimiento: 27 mesesLEN, lenalidomide; NDMM, newly diagnosed multiple myeloma; OS, overall survival; PD, progressive disease; PFS, progression-free survival; pt, patient; TE,
transplant-eligible;
TNE, transplant non-eligible.
Jackson GH, et al. Lenalidomide is a Highly Effective Maintenance Therapy in Myeloma Patients of all Ages: Results of the Phase III Myeloma XI Study. ASH 2016,
abstract 1143.
MMND
Elegibles y no
elegibles a TAPH
Tratados en
protocolos de
inducción Myeloma XI
N = 1551
Tratamiento
hasta PE
LEN
Mantenimiento
LEN 10 mg D1–21
28-day cycles
No
Mantenimiento
RA
ND
OM
IZA
CIO
N 1
:1
Myeloma XI: LEN Mantenimiento en MMND
SLP según riesgo citogenético
• Se observó un beneficio en SLP en pts con alto riesgo citogenético en
mantenimiento con LEN frente al no mantenimiento
LEN, lenalidomide; NDMM, newly diagnosed multiple myeloma; PFS, progression-free survival; pt, patient.
Jackson GH, et al. Lenalidomide is a Highly Effective Maintenance Therapy in Myeloma Patients of all Ages: Results of the Phase III Myeloma XI Study.
ASH 2016, abstract 1143.
33
LEN Maintenance After ASCT in MM: OS AnalysisMethods
• A meta-analysis of RCTs was prospectively planned with the
following inclusion criteria:
– A LEN maintenance arm vs a control arm (placebo or no maintenance)
after ASCT
– Database lock had previously occurred for primary efficacy analysis
– Primary patient-level source data were available
ASCT, autologous stem cell transplant; CALGB, Cancer and Leukemia Group B; GIMEMA, Gruppo Italiano Malattie EMatologiche dell'Adulto; IFM, Intergroupe Francophone
Multiple Myelome; LEN, lenalidomide; MM, multiple myeloma; OS, overall survival; RCT, randomized controlled trial.
McCarthy PL. IMW 2017, abstract #OP-010.
34
LEN Maintenance After ASCT in MM: OS AnalysisMethods
• A meta-analysis of RCTs was prospectively planned with the
following inclusion criteria:
– A LEN maintenance arm vs a control arm (placebo or no maintenance)
after ASCT
– Database lock had previously occurred for primary efficacy analysis
– Primary patient-level source data were available
ASCT, autologous stem cell transplant; CALGB, Cancer and Leukemia Group B; GIMEMA, Gruppo Italiano Malattie EMatologiche dell'Adulto; IFM, Intergroupe Francophone
Multiple Myelome; LEN, lenalidomide; MM, multiple myeloma; OS, overall survival; RCT, randomized controlled trial.
McCarthy PL. IMW 2017, abstract #OP-010.
17 studies identified
4 studies randomized
LEN maintenance vs
control arm
3 studies fulfilled all criteria:
IFM 2005-02
CALGB 100104 (Alliance)
GIMEMA RV-MM-PI-209
13 studies
No control arm
1 study
Myeloma XI UK
(not completed)
Search of LEN
maintenance studies
35
LEN Maintenance After ASCT in MM: OS AnalysisOS (Median Follow-Up, 80 mos)
• There is a 25% reduction in risk of death, representing an estimated
2.4-yr increase in median survival (March 2015 data cutoff)a
a Log-rank test and Cox model stratified by study to assess impact of LEN maintenance on OS. Median for LEN treatment arm was extrapolated to be 115 mos based on median
of the control arm and HR (median, 86 mos; HR = 0.75).
ASCT, autologous stem cell transplant; HR, hazard ratio; LEN, lenalidomide; maint, maintenance; MM, multiple myeloma; NR, not reached; OS, overall survival.
McCarthy PL. IMW 2017, abstract #OP-010.
36
LEN Maintenance After ASCT in MM: OS AnalysisOS: Hazard Ratios
• Individual HRs are in the same direction, favoring LEN maintenance effect
– All studies contribute to the positive results of the meta-analysis
• No qualitative heterogeneity (P = .75)
• Quantitative heterogeneity (P = .047)a The size of the box is related to the size of the individual study. The confidence interval is a function of the overall sample size.
ASCT, autologous stem cell transplant; HR, hazard ratio; LEN, lenalidomide; maint, maintenance; MM, multiple myeloma; OS, overall survival.
McCarthy PL. IMW 2017, abstract #OP-010.
LEN Maintenance After ASCT in MM
• LEN maintenance significantly prolongs OS post-ASCT (estimated 2.4-
yr improvement in median OS)
• LEN maintenance after ASCT can be considered a standard of care
• Developing early endpoints as surrogates for long-term outcome and
OS, particularly MRD-negativity, is critically important for the future.
• Otherwise, incorporation of new and efficacious therapies into clinical
practice will be significantly delayed
ASCT, autologous stem cell transplant; HR, hazard ratio; LEN, lenalidomide; MM, multiple myeloma; OS, overall survival.
1. McCarthy PL. IMW 2017, abstract #OP-010. 2. Attal M. J Clin Oncol. 2016;34(suppl):8001.