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www.comtecmed.com/comy | comy@comtecmed.com
Evangelos Terpos, MD, PhD
Clinical Case Study Discussion:
Maintenance in MM
Disclosure of Conflict of Interest (List)
Honoraria Celgene, Janssen-Cilag
National & Kapodistrian University of Athens,
School of Medicine, Athens, Greece
61-year-old female presents with acute
back pain that has persisted for 1 month
• Evaluations in the
orthopedics clinic revealed
– A fracture in L4
– DXA-scan T-score of the
lumbar spine: -2.8
– hemoglobin 10.5 g/dL
– serum protein
electrophoresis: 25 g/L
IgG-kappa
• Referral to the hematology
clinic
Patient diagnosed with multiple myeloma, IgGk, ISS-2
Patient workup and diagnosis
• Evaluations in the hematology clinic revealed
– skeletal survey (WBXR): no osteolytic lesions, only
diffuse osteoporosis, L4 fracture
– WBC 2.7 x 109/L
– hemoglobin 10.6 g/dL
– platelets 175 x 109/L
– creatinine 101 µmol/L (1.1 mg/dL)
– albumin 2.8 g/dL
– Kappa/lambda ratio: 8.4
– Electrophoresis of the urine: 95% of k-light chains
– FISH analyses revealed t(4;14) translocation
– BM plasma cells: 35% plasma cells
– β2M 3.2 mg/L
At this point would you treat the patient?
A. The patient has asymptomatic myeloma (no CRAB)
criteria and needs close follow-up
B. The patients has symptomatic myeloma and
requires immediate treatment
C. The patient has an osteoporotic fracture and needs
only bisphosphonate administration
D. The patient has high-risk asymptomatic myeloma
and needs treatment with RD (lenalidomide and
dexamethasone)
Case continue
An MRI of the spine was performed: several focal
lesions were revealed
Hillengass et al. J Clin Oncol 2010;28:1606-10
149 patients
Focal lesions: 28%
The presence of
focal lesions was
the strongest
adverse prognostic
factor for
progression into
symptomatic
disease (p<0.001)
Algorithm for Imaging in our Center
Suspected plasmacytoma or
myeloma Soft tissue mass
Suspected spinal cord
compression
CT scan
and consider biopsy Radiological
Skeletal Survey and WBCT
Urgent MRI/CT scan
and appropriate
medical management
Lytic Lesions Present?
Yes No
Whole Body CT/LS & pelvis MRI Risk for fracture?
Yes No
Urgent orthodedic review;
consider radiotherapy Systemic Therapy
Lytic Lesions >1
Diffuse pattern
0-1 Focal Lesions
0-1 Lytic Lesions
No Diffuse pattern
Observation
?
Case continue
• The patients was treated with VTD x 4, high dose
melphalan with ASCT
• Zoledronica acid was also given
• She achieved a vgPR post-induction and CR post-
ASCT: the M-component was present only in
serum immunofixation
• Grade 2 painful peripheral neuropathy was
present post-ASCT
Would you continue the treatment at this
point?
A. No, the patient has achieved a CR and does not
need further anti-myeloma treatment; I will follow-up
him every month with zoledronic acid
administration only
B. The patient has high-risk myeloma and I will give
maintenance with thalidomide
C. The patient has high-risk myeloma and I will give
lenalidomide maintenance
D. The patient has shown significant improvement with
the given therapy and I will continue on VTD
consolidation plus zoledronic acid with no
maintenance afterwards
E. The patient needs a second auto-transplant
Answer E: Single versus double ASCT in MM IFM94 trial
VGPR after first ASCT Absence of VGPR after first ASCT
P<0.001
P=0.7
Attal et al. N Engl J Med 2003;349:2495-502
Double vs single ASCT after bortezomib-based
induction: Integrated analysis of phase European 3 studies
• Pts (n=606)
– Bortezomib-based induction
– Single (n=254) or double (n=352) ASCT
• Differentiation of 4 groups based on adverse prognostic variables:
– ISS 3, high-risk cytogenetics, failure to achieve CR after induction
therapy
• Group 0 (13%): ISS 1-2, lack of high-risk cytogenetics, CR after induction
• Group 1 (61%): one adverse variable
• Group 2 (23%): two adverse variables
• Group 3 (3%): all three adverse variables
Cavo et al. ASH 2013 (Abstract 767), oral presentation
Double vs single ASCT after bortezomib-based
induction: Integrated analysis of phase European 3 studies
Group 0
(no adverse
variable)
Group 1
(1 adverse
variable)
Group 2
(2 adverse
variables)
Group 3
(3 adverse
variables)
Median PFS 61 months 56 months 36 months 26 months
• Presence of 2 (P<0.001) or 3 (P<0.001) adverse prognostic
variables associated with progressively shorter OS compared to lack
of all 3 adverse variables
Adverse variables: ISS 3, high-risk cytogenetics, failure to achieve CR after induction therapy
Cavo et al. ASH 2013 (Abstract 767), oral presentation
Double vs single ASCT after bortezomib-
based induction PFS and OS in patients with 2 adverse variables
Cavo et al. ASH 2013 (Abstract 767), oral presentation
PFS and OS for pts with high-risk cytogenetics and who failed CR
after bortezomib-based induction regimens
Double ASCT Single ASCT P
PFS 41 months 20 months 0.003
OS 67 months 31.5 months <0.001
PFS OS
Randomization
Induction (three 21-day cycles)
• Bortezomib-Thal-Dex (VTD)
V 1.3 mg/m2 d1, 4, 8, 11
T 200 mg daily
D 320 mg/cycle
Double ASCT
Consolidation (two 35-day cycles)
• Bortezomib-Thal-Dex (VTD)
V 1.3 mg/m2 once-weekly
T 100 mg/d through d 1 to 70
D 320 mg/cycle
Induction (three 21-day cycles)
• Thal-Dex (TD)
T 200 mg daily
D 320 mg/cycle
Consolidation (two 35-day cycles)
• Thal-Dex
T 100 mg/d through d 1 to 70
D 320 mg/cycle
Answer D: VTD consolidation
Study design (Gimema-MMY-3006)
n=236 n=238
Maintenance: Dex
Cavo et al. Lancet 2010;376(9758):2075-85
Cavo et al. Blood 2012;120(1):9-19
Cavo et al. ASH 2013 (Abstract 2090), poster presentation
PFS PFS for pts with
t(4;14) and/or del(17p)
PFS for pts with or
without t(4;14)
PFS from starting
consolidation
Cavo et al. ASH 2013 (Abstract 2090), poster presentation
VTD vs TD incorporated into double ASCT: Updated analysis of Phase 3 Gimema-MMY-3006 study
Do we need a bisphosphonate together
with VTD consolidation?
• VTD started on day 100 post-
ASCT
• patients received 4 cycles of
VTD (1st block), were followed
without treatment for 100
days and then received
another 4 VTD cycles (2nd
block)
• during this 12-month period,
BPs were not administered.
• only one patient with PD
developed a skeletal-related
event (i.e. radiation to bone)
N=42
• Best response:
CR 36%, CR 31%,
vgPR 16.5%, PR 9.5%, PD 7%
• 33% and 47% of patients
improved their status of
response after the 1st and 2nd
VTD block, respectively
• median TTP after ASCT was 34
months
• median TtNT was 40 months
Terpos et al. Leukemia 2014;28:928-34
Phase 3 trial: Bortezomib monotherapy
as consolidation (Nordic Myeloma Study Group [NMSG 15/05] trial)
Induction (no bortezomib) + single or double ASCT (n=403)
Randomization (3 months post-ASCT) (n=370)
Bortezomib (n=187)
1.3 mg/m2 IV
Two 3-week cycles: days 1, 4, 8, 11
+
Four 4-week cycles: days 1, 8, 15
(total 20 injections over 21 weeks)
Observation (n=183)
Primary objective: PFS
Mellqvist et al. Blood 2013;121:4647-4654
Bortezomib Control p value
Improvement of response from
PR to ≥ VGPR 57% 36% 0.007
Median PFS 27 months 20 months 0.05
Incidence of neuropathy CTC ≥ III
Neuropathic pain > grade 2 6% 1% < 0.006
Sensory neuropathy > grade 2 5% 1% < 0.04
Bortezomib Monotherapy as Consolidation:
Results
• Median follow-up: 38 months
• Beneficial effect of bortezomib consolidation on PFS only seen
in patients not achieving at least VGPR after ASCT
Mellqvist et al. Blood 2013;121:4647-4654
Bortezomib Control p value
Improvement of response from
PR to ≥ VGPR 57% 36% 0.007
Median PFS 27 months 20 months 0.05
Incidence of neuropathy CTC ≥ III
Neuropathic pain > grade 2 6% 1% < 0.006
Sensory neuropathy > grade 2 5% 1% < 0.04
Bortezomib Monotherapy as Consolidation:
Results
• Median follow-up: 38 months
• Beneficial effect of bortezomib consolidation on PFS only seen
in patients not achieving at least VGPR after ASCT
Mellqvist et al. Blood 2013;121:4647-4654
VAD/HDM/Thalidomide PAD/HDM/Bortezomib
N PFS at
36 Mos, %
OS at
36 Mos, %
N PFS at
36 Mos, %
OS at
36 Mos, %
All 305 42 71 308 48 78
-13/13q- 126 29 59 112 44 82
t(4;14) 28 22 43 26 32 65
17p- 32 16 19 15 27 60
P < .01 in univariate analysis
All data FISH, -13/13q- also karyotype if available
Bortezomib maintenance therapy Phase 3 HOVON/GMMG trial
Sonneveld et al. J Clin Oncol 2012;30:3654
VAD PAD
goodintermediatepoor
N468330
D6
3724
good
intermediatepoor
At risk:468330
447322
436818
41549
39488
31355
19132
531
good
intermediate
poor
0
25
50
75
100
months0 12 24 36 48 60 72 84
Cum
ula
tive p
erc
enta
ge
goodintermediatepoor
N567327
D122815
good
intermediatepoor
At risk:567327
506723
496019
475516
444616
383810
27114
1030
good
intermediate
poor
0
25
50
75
100
months0 12 24 36 48 60 72 84
Cum
ula
tive p
erc
enta
ge
Bortezomib improves outcome in patients
with intermediate/poor risk based on FISH/ISS
Good Risk: no t(4;14)/del17p/add1q and ISS 1
Intermediate Risk: either t(4;14)/del17p/add1q and ISS 1
or no t(4;14)/del17p/add1q and ISS 2/3
Poor Risk: t(4;14)/del17p/add1q and ISS 2/3
Sonneveld et al. ASH 2013 (Abstract 404), oral presentation; Neben et al. Blood 2012;119(4):940-8.
Overall survival by risk group (FISH + ISS)
Significant improvement in
PFS with maintenance
therapy
Significant improvement in
OS with maintenance
therapy
Survival after
relapse
Spencer Yes Yes
(3 years follow up) Similar in all groups
Attal Yes
Yes (@ 39 m),
but OS advantage
disappeared with longer
follow-up (5.7 years)
Similar in all groups
Barlogie Yes Yes
(7.2 years follow-up)
Reduced OS after
thal exposure
Lokhorst Yes No Reduced OS after
thal exposure
Morgan Yes No Reduced OS after
thal exposure
Stewart Yes No Reduced OS after
thal exposure
Answer 3: Thalidomide maintenance therapy
Spencer et al. J Clin Oncol 2009;27:1788-93; Attal et al. Blood 2006;108:3289-94;
Barlogie et al. N Engl J Med 2006;354:1021-30; Blood 2008;112:3115-21;J Clin Oncol 2010;28:1209-14; Lokhorst et al. Blood
2010; 115: 1113-20; Morgan et al. Clin Cancer Res 2013;19:6030-8; Stewart et al. Blood 2013;121:1517-23
ALLG MM6 study Updated results
TP versus P: Survival benefit is durable
5yr PFS: 27% vs 15%
HR 0.16; 95% CI 0.044 to 0.582
5yr OS: 66% vs 47%
HR 0.12; 95% CI 0.028 to 0.558
Progression Free Survival Overall Survival
TA
CA
TA
CA
Kalff et al. HSANZ 2013 (oral presentation)
Median follow-up: 5.4 years
Pts (n=243), newly diagnosed MM
Treatment: Single ASCT
Randomization: Thal/Pred (n=114) vs Pred (n=129)
At least 8 months of thalidomide is
required for PFS and OS benefit
8-12m vs CA p<0.001
8-12m vs <8m p=0.032
8-12m vs CA p<0.001
8-12m vs <8m p=0.013
Progression Free Survival Overall Survival
TA <8m
TA 8-12m
CA
TA <8m
TA 8-12m
CA
Kalff et al. HSANZ 2013 (oral presentation)
Answer B: Lenalidomide maintenance (IFM 2005-02)
Arm A=
Placebo
(n=307)
until relapse
Patients < 65 years, with non-progressive disease,
6 months after ASCT in first line
Arm B=
Lenalidomide
(n=307)
10-15 mg/d until relapse
Primary end-point: PFS. Secondary end-points: CR rate, TTP, OS, feasibility of long-term lenalidomide
Phase 3 randomized, placebo-controlled trial n= 614 patients, from 78 centers, enrolled between 7/2006 and 8/2008
Consolidation:
Lenalidomide alone 25 mg/day p.o.
days 1-21 of every 28 days for 2 months
Randomization: stratified according to Beta-2m, del13, VGPR
Attal et al. N Engl J Med 2012;366(19):1782-91.
PFS and OS data IFM 2005-02: Lenalidomide maintenance
• Median follow-up: 67 months (from randomization)
Lenalidomide
n=307
Placebo
n=307 P
PFS 46 months 24 months 0.001
OS 82 months 81 months 0.8
Attal et al. ASH 2013 (Abstract 406), oral presentation
0.0
00
.25
0.5
00
.75
1.0
0
0 6 12 18 24 30 36 42
Placebo Revlimid
0.0
00
.25
0.5
00
.75
1.0
0
0 6 12 18 24 30 36 42
Placebo Revlimid
PFS according to Response Post-ASCT
HR= 0.31 - CI 95% [0.14-0.68] HR= 0.50- CI 95% [0.38-0.65]
CR Not in CR
p=0.021 p<0.0001
Rev
Placebo
Rev
Placebo
Attal et al. N Engl J Med 2012;366:1782-91
Lenalidomide maintenance in high-risk
cytogenetics
• Patients treated in 2005-01 trial: Vel/dex vs VAD
• Patients achieving ≥ PR post-transplantation enrolled in 2005-02 trial:
2 months consolidation with lenalidomide followed by lenalidomide
maintenance or placebo
• Chromosomal data available for 488 patients:
– t(4;14) in 13.3%
– del(17p) in 6.6%
• Within lenalidomide arm, PFS comparison for patients with or without
t(4;14) or del(17p) showed significant difference, in favor of ‘no
abnormality’ group: The median PFS of the total group of Len treated
patients was 42m
Lenalidomide maintenance Placebo
Median PFS for pts with t(4;14) 27 months 15 months
Median PFS for pts with del(17p) 29 months 14 months
Avet-Loiseau et al. ASH 2010 (Abstract 1944)
Lenalidomide maintenance therapy: CALGB 100104 Update at IMW 2013
• Cumulative incidence of second primary cancers greater in
lenalidomide group (P=0.034)
• Cumulative incidence of risk of PD (P=0.004) and death
(P<0.001) greater in placebo group
Lenalidomide arm Placebo arm P
Median EFS 47 months 27 months <0.001
Events: PD, death, SPM
McCarthy P. IMW 2013, oral presentation (S15 Consolidation / Maintenance)
Phase 3: MPR vs tandem ASCT,
Len maintenance vs no treatment
• Pts (n=402) with newly diagnosed MM <65 years
Gay et al. ASH 2013 (Abstract 2089), poster presentation
PFS and OS: Len maintenance vs no
treatment
Gay et al. ASH 2013 (Abstract 2089), poster presentation
4-year OS:
Len maintenance 80%
No maintenance 62%
Median PFS:
Len maintenance 42.7 mos
No maintenance 17.5 mos
PFS
OS
No maintenance
No
maintenance
R maintenance
R maintenance
Lenalidomide maintenance:
Meta-analysis of randomized trials
• 4 phase 3 trials (3 publications and 1 abstract) (n= 1935):
– IFM 05-02, CALGB 100104, RV-MM-PI209 (transplant setting)
– MM-015 (non-transplant setting)
– Analysis of entire treatment package (not only maintenance)
• Findings
– Len maintenance is associated with
• improvement in PFS
• trend towards improved OS
• increased risk of grade 3-4 AEs and SPMs
– Subset of pts benefiting from Len maintenance not yet defined
– Careful discussion with patient required
Singh et al. ASH 2013 (Abstract 407), oral presentation
Who might benefit from continued
therapy?
Implications of continued response after ASCT Retrospective analysis
• Pts (n=430) who underwent ASCT within 12 months of diagnosis
– Excluded: pts in CR at day 100 or who had received maintenance
• Comparison of patients with and without continued response after day 100
without additional therapy
• Results
• Multivariate analysis: lack of continued response predicted for worse PFS
and OS
• Conclusions
– Continued response post-ASCT is prognostic
– Possible clinical implications on the use of post-transplant therapy
Continued response
(n=167)
No continued response
(n=263) P
PFS 35 months 13 months <0.001
TTNT 43 months 16 months <0.001
OS 96 months 57 months <0.001
Gonsalves et al. Blood 2013;122(10):1746-1749
Who might benefit from post-ASCT
therapy?
• High-risk disease by FISH and GEP associated with poor OS Chng et al. Leukemia 2013 Aug 26 [Epub ahead of print]
Avet-Loiseau et al, Blood 2007;109: 3489-3495
Shaughnessy et al. Blood 2007;109: 2276-2284
Decaux et al. J Clin Oncol 2008;26:4798-4805
Dickens et al. Clin Cancer Res 2010;16(6);1856–64
Moreaux et al. Haematologica 2011;96(4):574-582
Broyl et al. Blood 2010;116(14):2543-53
• ISS 3, high LDH and t(4;14) and/or del(17p) as a prognostic index
for OS
– Scoring system to identify pts with very high-risk disease and
short survival due to PD Moreau et al. IMW 2013 (Abstract O-13), oral presentation
Who might benefit from post-ASCT
therapy?
• High serum-free light chain levels and their rapid reduction in
response to therapy define an aggressive MM subtype with poor
prognosis
– SFLC baseline levels higher than 75 mg/dL identified pts with
higher nCR to induction therapy, yet inferior EFS and OS Van Rhee et al. Blood. 2007; 110:827-832
• Early responder myeloma: kinetic studies identify patient subgroup
characterized by poor prognosis
– Early response associated with high plasma cell proliferative
activity is a poor prognostic factor Boccadoro et al. J Clin Oncol 1989;7(1):119-25
– Shorter remission duration and OS in pts who had an initially
rapid response to therapy Belch et al. Br J Cancer 1988;57(1):94-9
Who might benefit from post-ASCT
therapy?
• Sustained CR independent favorable post-treatment variable
associated with prolonged OS
– Loss of CR associated with adverse prognosis
Barlogie et al. Cancer 2008;113:355–9
Hoering et al. Blood 2009; 114(7): 1299–1305
• Long-term survival despite absence of CR
– Persistent small levels of M-protein and minimal marrow
plasmacytosis (likely regression to an MGUS phase)
Fassas et al. Bone Marrow Transplant 2005;35(3):215-24
Study case continue….
• The patient received lenalidomide maintenance for 5
years
• Achieve sCR
• Suddenly a dramatic reduction in FBC values
• RAEB-II was diagnosed
• Currently on Vidaza (acatydidine) 75 mg/m2 seven
days per month
• MDS in PR
Summary / Conclusions
• Consolidated data confirm PFS and OS benefit of
bortezomib-based induction therapy
• Consolidation with VTD improves depth of response and
PFS
• Maintenance therapy:
– Thalidomide: improvement in PFS and OS
– Lenalidomide: improvement in PFS (2 studies) and OS
(1 study), but reduced OS post-relapse (1 study)
– Bortezomib: improvement in OS
• We need further studies to better define the subgroups of
patients who will be benefited for a post-ASCT
continuous therapy strategy
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