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Friday, December 2, 2016San Diego, California
Treatment Advances in Multiple Myeloma: Expert Perspectives on Translating Clinical Data to Practice
This program is supported by educational grants from Amgen, Celgene Corporation, Karyopharm, Takeda Oncology, and The Binding Site.
Image: Copyright©2016 DNA Illustrations. All Rights Reserved
Program Director
Brian G.M. Durie, MDMedical Director, AMyCCo-Chair Myeloma Committee, SWOG Chairman, International Myeloma FoundationSpecialist in Multiple Myeloma and Related Disorders Cedars-Sinai Outpatient Cancer CenterLos Angeles, California
Brian G.M. Durie, MD, has disclosed that he has received consulting fees from Celgene, Johnson & Johnson, Onyx, and Takeda
Jesús F. San-Miguel, MD, PhDDirector of Clinical and Transnational MedicineClinica Universidad de NavarraUniversidad de NavarraPamplona, Spain
Jesús F. San-Miguel, MD, PhD, has disclosed that he has received consulting fees, honoraria, and fees for non-CME/CE services received directly from a commercial interest or their agents (eg, advisory board) from Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, and Novartis.
Faculty
Bruno Paiva, PhDDepartment of Hematology and ImmunologyFlow Cytometry Core - CIMA LAB DiagnosticsUniversity of NavarraPamplona, Spain
Bruno Paiva, PhD, has disclosed that he has received consulting fees from Celgene, Janssen, Merck, Novartis, and Takeda; funds for research support from Celgene and EngMab; and other honorarium for lectures from Amgen, Celgene, Janssen, and Takeda.
Faculty
ModeratorBrian G.M. Durie, MD
Faculty PresentersJesús F. San-Miguel, MD, PhD Bruno Paiva, PhD
How Should We Use Maintenance for Patients in Clinical Practice?
Image: Copyright©2016 DNA Illustrations. All Rights Reserved
Pt Case Example
65-yr-old male presents with:– 60% BM PCs
– 3.5 IgG-K M-spike (no immune paresis)
– High LDH
– ISS III
– t(4;14), no del(17p)
He enrolled in the phase III SWOG S0777 trial and was randomized to receive eight 21-day cycles of VRd
The pt is in CR at the end of induction
MRD was assessed after induction and was positive (10-5)
What would you recommend now?
A. Observation
B. Lenalidomide maintenance for up to 2 yrs
C. Lenalidomide maintenance until progression
D. Bortezomib maintenance for up to 2 yrs
E. ASCT followed by lenalidomide maintenance
F. ASCT followed by bortezomib maintenance
G. Unsure
Expert Recommendations
Expert RecommendationBrian G.M. Durie, MD ASCT followed by lenalidomide maintenanceShaji Kumar, MD ASCT followed by lenalidomide maintenancePhilippe Moreau, MD ASCT followed by lenalidomide maintenanceBruno Paiva, PhD ASCT followed by lenalidomide maintenanceS. Vincent Rajkumar, MD ASCT followed by bortezomib maintenanceJesús F. San-Miguel, MD, PhD ASCT followed by lenalidomide maintenance
Role of Maintenance Therapy in Multiple Myeloma
Jesus San-Miguel, MD, PhDUniversity of Navarra, Spain
Consolidation• Improve response/deeper
following therapy– By administration of treatment
for a limited period
Maintenance• Maintain response achieved
following therapy– By administration of treatment
for a prolonged period
What is the goal of consolidation ormaintenance therapy??
Young, transplant candidate pts
Elderly pts
Role of Maintenance Therapy in Multiple Myeloma
Maintenance is not a new concept …...in the 90‘s IFN was used following ASCTand pulses of MP to maintain the response
Maintenance Treatment With Thalidomide*
Caveats: Role in CR, duration of maintenance, toxicity, outcome after relapse
1. Spencer A et al. IMWG 2013 Kyoto2. Attal M et al. Blood. 2006;108:3289.3. Barlogie B et al. N Engl J Med. 2006;354:1021.4. Barlogie B et al. Blood. 2008;112:3115.
6 randomized trials have compared thalidomide ± pred vs nothing orpamidronate or prednisone or IFN
> PFS in all 6 trials…………….. but improved OS in only 3 Meta-analysis: modest benefit in PFS and OS (± 6 m)
5. Lokhorst HM et al. Blood. 2010;115:1113. 6. Morgan GJ, et al. Blood. 2012;119:7.7. Stewart AK et al. Blood. 2010;116: Abstract 39.
1. Sonneveld P, et al. J Clin Oncol. 2012;30:2946. 2. Rosiñol, et al. ASH 2012; Abstract 334.
Maintenance With Bortezomib-Based Therapy
Study DetailsMedian
f/uResults
≥ nCR ≥ VGPR PFS OSPAD/HDM/bortezomib[1]
vs
VAD/HDM/thalidomide
41 m
49%*
34%
76%*
56%
35 m*
28 m
Median not reached
HR: 0.77 (0.60-1.00)
P = .049
Induction/HDM/ bort + thal vs thal vs IFN x 3 yrs[2]
24 m 74% — 50.6 m**40.3 m32.5 m
78% @ 5 y72%70%
*Significant difference between arms**Median fw 58,6 m , P = .03IFN: 3 MU/sc 3 times a wk. Thal: 100 mg/day. Bort: one cycle/3 mos.
Lenalidomide vs Placebo After ASCT: PFS From Randomization
2nd Malignancies: 6,5% vs 2%
Attal, M. N Engl J Med. 2012;366:1782-1791. (Updated Feb 2015)
0.0
00.2
50.5
00.7
51.0
0
0 6 12 18 24 30 36
Placebo Revlimid
OS: 75% at 5 yrs in both arms
Len
Placebo
46 m
24 m
P < 10-8
IFM 2005-02PFS
2nd Malignancies: 8 vs 3%
McCarthy P. N Engl J Med. 2012;366:1770-1781. (Updated Nov 2014)
Len
Placebo
53 m
26 m P < 10-8
CALGB 100104
Median OS: 76 vs NR, P = .001
PFS PFS
Len
Placebo
37 m
26 m
4-yr OS: 80% vs 62%, P = .02
GIMEMA MM-RV-209
Palumbo, et al. N Engl J Med. 2014;371:895-905.(Gay ASH 2013; Abstract 2081)
Meta-Analysis of Overall Survival WithLenalidomide Maintenance: Median Follow-up of 80 m
0.00 10 20 30 40 50 60 70 80 90 100 110 120
0.2
0.4
0.6
0.8
1.0
26% reduction in risk of death, representing an estimated 2.5-yr increase in median survivala
605 578 555 509 474 431 385 282 200 95 20 1 0604 569 542 505 458 425 350 271 174 71 10 0
Overall Survival, mos
Surv
ival
Pro
babi
lity
Pts at risk
7-yr OS
62%
50%N = 1209 LENALIDOMIDE CONTROLMedian OS, mos (95% CI)
NE(NE-NE)
86.0(79.8-96.0)
HR (95% CI) 0.74 (0.62-0.89) P =. 001
a Median for lenalidomide treatment arm was extrapolated to be 116 mos based on median of the control arm and HR (median: 86 mos; HR: 0.74).
Attal M, et al. ASCO 2016. Abstract 8001. HR, hazard ratio; NE, not estimable; OS, overall survival.
LENa CONTROLa HR (95% CI)
Age 372 375 0.68 (0.54-0.86)233 229 0.83 (0.63-1.10)
Sex 322 349 0.65 (0.52-0.83)283 255 0.91 (0.69-1.19)
ISS stage 411 440 0.65 (0.52-0.81) 113 90 1.04 (0.72-1.51)
Response after ASCT66 80 0.63 (0.35-1.16)
320 339 0.70 (0.54-0.90)218 210 0.86 (0.65-1.15)
Prior induction therapy 147 146 0.48 (0.31-0.75)458 458 0.82 (0.67-1.00)
Adverse-risk cytogeneticsb 56 36 1.18 (0.66-2.10)231 243 0.79 (0.59-1.06)
CrCl after ASCTc 33 25 0.73 (0.33-1.60)379 404 0.74 (0.59-0.92)
Overall Survival: Subgroup Analysis
a Number of pts. b Cytogenetic data were available only for the IFM and GIMEMA studies. c CrCl post-ASCT data were available only for the CALGB and IFM studies.ASCT, autologous stem cell transplant; CR, complete response; CrCl, creatinine clearance; HR, hazard ratio; ISS, International Staging System; LEN, lenalidomide; OS, overall survival; PD, progressive disease; PR, partial response; SD, stable disease; VGPR, very good partial response.
Favors controlFavors LEN
Attal M, et al. ASCO 2016. Abstract 8001.
Myeloma XI: Trial Design
Non-Intensive PathwayRandomize
1:1CTD RCD
Assess Response
NC + PD CR + VGPR PR + MR
CVD
Randomise
Assess Response
Assess Response
No maintenance
High-Dose Melphalan & ASCT
ASCT, autologous stem cell transplant; CR , complete response; CTD , cyclophosphamide (500mg p.o. D1,8,15), thalidomide (100-200mg p.o. daily), dexamethasone (40mg p.o. D1-4, 12-15); CTDa, cyclophosphamide (500mg p.o. D1,8,15, 22), thalidomide (50-200mg p.o. daily), dexamethasone (20mg p.o. D1-4, 15-18); MR, minimal response; NC, no change; PD, progressive disease; PR, partial response; RCD, cyclophosphamide (500mg p.o. D1,8,15), Lenalidomide (25mg p.o. D1-21), dexamethasone (40mg p.o. D1-4, 12-15); RCDa , cyclophosphamide (500mg p.o. D1,8), Lenalidomide (25mg p.o. D1-21), dexamethasone (20mg p.o. D1-4, 15-18); VCD, Bortezomib, cyclophosphamide, dexamethasone; VGPR , very good partial response.
1. Rev (15.07.2014) Myeloma X1 Trial Protocol v5
Maintenance Randomization**
Lenalidomide 10 mg
maintenance
Lenalidomide 10 mg + Vorinostat
300 mg maintenance
Randomize 1:1
CTDa RCDa
Assess Response
NC + PD CR + VGPR PR + MR
CVD CVDNothing
Randomise
Assess Response
Assess Response
No maintenance
Maintenance Randomization
Lenalidomide 10 mg
maintenance
Lenalidomide 10 mg + Vorinostat
300 mg maintenance
**Pts entered into the RCD arm and assessed as NC or PD at the end of RCD induction are not eligible for the maintenance randomisation
Intensive Pathway
ASH2016 abstracts
CVDNothing
Jackson, et al. ASH2016. Abstract 1143.
0
10
20
30
40
50
60
70
80
Len maint. No maint.
PFS
, mos
HR 0.46; P < .0001
Post-ASCT
05
10152025303540
Len maint. No maint.P
FS, m
os
HR 0.44; P < .0001
NSCT
60
28
26
12
Myeloma XI: PFS Len Maintenance vs No Maintenance Median Follow-up: 26 mos
• Primary endpoint maintenance comparison: PFS and OS• Len maintenance doubles PFS vs no maintenance: 55% reduction in the risk of progression or death
– Median PFS 37 vs 19 mos (HR: 0.45 [95% CI: 0.39-0.52], P < .0001)• Significant improvement in PFS was observed in each pathway and across subgroups • Main grade 3/4 AEs: neutropenia (35%), thrombocytopaenia (7.4%), anaemia (4.4%), PN (1.4%) • SPMs: Hematologic incidence 0.3% vs 0.9%; slight excess in older pts, mostly noninvasive and did not
impact outcome benefit demonstrated
4 Independent Phase III Clinical Trials Investigated Lenalidomide Maintenance Post-ASCT
Coop trial PFS Hazard Ratio
IFM2005-02[1] 0.50
CALGB 100104[2] 0.48
GIMEMA RV-209[3] 0.44
Myeloma XI[4] 0.45
1. Attal M, et al. NEJM 2012;366:1782-91.2. McCarthy P, et al. NEJM 2012;366:1770-81.3. Palumbo A, et al. NEJM 2014;371:895-905.4. Jackson, et al. ASH2016. Abstract 1143.
Is there any role for maintenance therapy?
Elderly MM Patients
Thalidomide: Effect of Maintenance on PFS/OS
Study Regimen N CR (IF–) TTPPFS/EFS Overall Survival
Palumbo (Blood 2008;112:3107)
MPT (T maint.)MP (no maint.)
129126
16%4%
21.8 m14.5 m
NS: 45 m vs 47.6 mP = .79
Wijermans(JCO 2010;28:3160)
MPT (T maint.)MP (no maint.)
165168
2%2%
13 m9 m
40 m vs 31 mP = .05
Waage A(Blood 2010;116:1405)
MPT (T maint.)MP (no maint.) 363 13%
4%15 m14 m
NS: 29 m vs 32 mP = .35
• Thal-IFN vs IFN alone after induction with Thal/Dex or MP:Benefit in PFS but not in OS (Ludwig H. Haematologica 2010)
• Thal vs no maintenance after induction with CTDa or MP:Benefit in PFS (11m vs 9 m) but not in OS (Morgan G. Blood 2012)
Duration of Thal maintenance therapy short, due to toxicity.
HR 0.63, 95% CI, 0.46-0.88, p =.006
4-years OS Median OS
VMP
VMPT-VT
55% 54.2 months
67% Not reached
4-years OS Median OS
VMP
VMPT-VT
55% 54.2 months
67% Not reached
0.00
0.25
0.50
0.75
1.00
0 10 20 30 40 50 60 70
0.00
0.25
0.50
0.75
1.00
0 10 20 30 40 50 60 70
Pat
ient
s (%
)
Time (months)
Influence of Maintenance: VMPT + VT vs VMP
Palumbo A, et al. J Clin Oncol. 2010;28:5101-5109.
Median PFS: 37 m
VT continuous therapyVMPT
0
25
50
75
100
0 10 20 30 40 50
VMP
VMPT-VT
P < .0001
HR: 0.48
CR (IF–) after VMPT->VT increased up to 42% (maintenance)
VMP
VMPT-VT
4-y OS: 67%
VT continuous therapyVMPT
0
100
Pat
ient
s (%
)
25
50
75
0 10 20 30 40 50 60 70MonthsMonths
Pat
ient
s (%
)
Bortezomib ± Thalidomide MaintenanceModified VMP vs VTP Followed by Maintenance With VT or VP in Newly Diagnosed Elderly Pts With MM (GEM2005)
CR (IF–) increased from 24% (after induction) up to 42% (maintenance)
Mateos MV et al. Blood. 2012;120:2581.
VISTA: PFS 21m VISTA: 5-y OS: 46%; Time in months from 1st randomization
OS
Time in months from 1st randomization
PFS
6050403020100
1.0
0.8
0.6
0.4
0.2
0.0
Pro
porti
on o
f Pts
VT: 39 m
VP: 32m
P=0.1
Pro
porti
on o
f Pts
VT: Not reached5-y OS: 69%
VP: 60m
P=0.1
6050403020100
1.0
0.8
0.6
0.4
0.2
0.0
OS
Lenalidomide MaintenanceMM-015: MPR-R vs MPR vs MP
Palumbo, et al. N Engl J Med. 2012;366:1759-1769.
Median PFS
MPR-R 31 mos
MPR 14 mos
MP 13 mos
No differences were observed so far in OS
HR 0.49 P < . 001
Time (mos)0 5 10 15 20 25 30 35 40
0
25
50
75
100
HR 0.40P < . 001
FIRST Trial: Len/Dex (18 Cycles or Continuous) vs MPT
Median PFSRd (n = 535) 26 mosRd18 (n = 541) 21 mosMPT (n = 547) 21.9 mos
Hazard ratioRd vs. MPT: 0.69; P = 0.0006Rd vs. Rd18: 0.70; P = 0.0001
Rd18 vs. MPT: 1.03; P = 0.70349
Time (months)
Pts
(%)
100
80
60
40
20
00 6 12 18 24 30 36 42 48 54 60
72 w
ks
PFS
Facon T, et al. ASH 2016. Abstr 241.Hulin C, et al. J Clin Oncol. 2016;Epub ahead of print.
100
80
60
40
20
00 6 18 24 30 36 42 48 54 6012 66 72
Pts
(%)
Median OSRd (n = 535) 59 mosRd18 (n = 541) 62 mosMPT (n = 547) 49 mos
Hazard ratio Rd vs MPT: 0.78; P = 0.002Rd vs Rd18: 0.91; P = 0.305Rd18 vs MPT: 0.83; P = 0.034
OS
SPM, %Solid tumourHaematological
6.00.8
6.90.4
5.96.2
Median follow-up 67 mos, data cutoff 21 Jan 2016PFS: Rd continuous vs MPT: HR 0.69 (0.59-0.79) P < .00001 OS: Rd continuous vs MPT: HR 0.78 (0.67-0.92) P = .0023
Time (months)
VMP (x9) + Len/Dex (x9): PFS and OSGEM/Pethema GEM2010 Trial
Median follow-up: 30 months (9-43)OS
Sequential : 72% at 3 yrs
Alternating: 74% at 3 yrs
PFS
Sequential: 32m
Alternating: 34 m
p=NS
20,0010,000,00
1,0
0,2
454035302520151050
1,0
0,8
0,6
0,4
0,2
0,0
group
454035302520151050
1,0
0,8
0,6
0,4
0,2
0,0 p=NS
VISTA: 21mFIRST: 26m (cont Rd); 21 m (Rd18)
VISTA: 68% at 3 yrsFIRST: 70% (cont Rd), 66% at (Rd18) 3 yrs
Mateos, et al. Blood. 2016;127:420-425.
Lenalidomide single agent
Len vs Len+Dex: To determine which of the dual mechanisms of lenalidomide action, antitumoral and immunomodulatory, is more effective at maintaining the response.
Len + PI (Ixazomib / Carfilzomib)
Len + PI + anti-CD38 or Elo??
Len + PD-L1 inhibition
Optimal Maintenance Treatment: Number of Agents and Duration
One, two, three drugs???
Maintenance Therapy After ASCT: Future
IFM/DFCI 20091 Len x 1 yr vs len until DP
ECOG-ACRIN E1A112 Len x 2 yr vs len until DP
Myeloma XI3 Len vs len + vorinostat vs no maintenance
PETHEMA GEM 20144 Len vs len + ixazomib x 2 yrs ( MRD+ Pts cont x 3y)
SWOG7 Len vs len+ ixazomib until DP
GMMG-HD65 Len-dex vs len-dex + elotuzumab
GIMEMA6 Len vs len + carfilzomib
BMT CTN 14018 Len vs len + vaccination
AFT-409 Len vs len + durvalumab vs len + daratumumab vs len + ACY241TOURMALINE-MM310 Ixazomib for up to 2 yrs vs placebo
HOVON 131 MM-IFM 2015-0111 Daratumumab vs placebo
1. NCT01208662 at www.clinicaltrials.gov. 2. NCT01863550 at www.clinicaltrials.gov. 3. NCT01554852 at www.clinicaltrials.gov. 4. NCT02406144 at www.clinicaltrials.gov. 5. NCT02495922 at at www.clinicaltrials.gov.6. NCT02203643 at www.clinicaltrials.gov. 7. SWOG S1606 study. 8. NCT02728102 at www.clinicaltrials.gov. 9. Alliance study proposal.10. NCT02181413 at www.clinicaltrials.gov. 11. NCT02541383 at www.clinicaltrials.gov.
+/- Dara
Induction Consolidation Maintenance
(except Dara arm)
GEM 2017 for Fit, Elderly Pts: VMP/Rd vs KRd +/- Dara
D
D
DRdDR
DR
How Should We Monitor Patients During Maintenance Therapy?
Bruno Paiva, PhD
The true value of CR relies on the MRD status, and CR without MRD is no better than PR
Prog
ress
ion-
free
surv
ival
(%)
Time from response assessment (mos)
MRD– (n=316) median PFS: 58 mosCR (n=128) median PFS: 24 mosnCR (n=96) median PFS: 21 mosPR (n=199) median PFS: 26 mos< PR (38) median PFS: 9 mos
MRD– vs CR: P <.001CR vs nCR: P =.127
Ove
rall
surv
ival
(%)
Time from response assessment (mos)
MRD– (n=316) median OS: 145 mosCR (n=128) median OS: 59 mosnCR (n=96) median OS: 63 mosPR (n=199) median OS: 59 mos< PR (38) median OS: 32 mos
MRD– vs CR: P <.001CR vs nCR: P =.657
P <.001 P <.001
GEM2000, GEM2005MENOS65, GEM2005MAS65, GEM2010MAS65 (n=777) Lahuerta JJ, et al. manuscript under review
MRD-positive MRD-positive
Clinical benefit after CR vs MRD negativity among pts with high-risk cytogenetics
Overall Survival
0.0 0.2 0.4 0.6 0.8 1.0 1.2
0.0 0.2 0.4 0.6 0.8 1.0 1.2
OverallTransplant eligibleTransplant ineligibleISS IISS IIISS IIIStandard-risk FISHHigh-risk FISH
HR 95% CI P0.37 0.29-0.47 < .0010.34 0.26-0.45 < .0010.53 0.34-0.82 .0040.26 0.16-0.43 < .0010.46 0.32-0.65 < .0010.46 0.29-0.75 .0020.39 0.28-0.55 < .0010.35 0.19-0.66 .001
Reduced risk after MRD–
HR 95% CI P0.62 0.53-0.72 < .0010.65 0.55-0.78 < .0010.58 0.42-0.82 .0020.59 0.44-0.79 < .0010.72 0.57-0.91 .0050.55 0.39-0.77 < .0010.66 0.50-0.87 .0040.76 0.44-1.32 .330
Reduced risk after CR
GEM2000, GEM2005MENOS65, GEM2005MAS65, GEM2010MAS65 (n=777) Lahuerta JJ, et al. manuscript under review
OverallTransplant eligibleTransplant ineligibleISS IISS IIISS IIIStandard-risk FISHHigh-risk FISH
CR
MRD
Time from MRD assessment at cycle 9 (months)
P <.001 P =.009
Time from MRD assessment at cycle 9 (months)
Tim
e to
pro
gres
sion
(%)
Ove
rall
surv
ival
(%)
MRD– (n=25), median TTP: NRCR & MRD+ (n=22), median TTP: NR<CR & MRD+ (n=80), median TTP: 15m
50403020100
100
80
60
40
20
0
50403020100
100
80
60
40
20
0
MRD– (n=25), 3y OS: 83%CR & MRD+ (n=22), 3y OS: 53%<CR & MRD+ (n=80), 3y OS: 58%
P =.13
P =.84
Paiva B et al. Blood 2016;127(25):3165-74
Can persistent MRD after induction be controlled with further treatment?
Another 9 cycles Another 9 cycles
Median time on maintenance in the Phase III Trial SWOG S0777: 385 days
Avet-Loiseau H, et al. Blood. 2015;126: Abstract 191.
What is the meaning of persistent MRDafter maintenance therapy
10-5 – 10-6
P value (trend) < .0001
[10-6; 10-5]
[10-5; 10-4]
≥ 10-4
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pts
With
out P
rogr
essi
on (%
)
0 6 12 18 24 30 36 42 48
Mos Since Randomization
MRD at postmaintenance
<10-6
MRD+ pts have different outcomes according to their cytogenetic profile
Standard-risk FISH / MRD– (n=40); median TTP: NR
High-risk FISH / MRD– (n=7); median TTP: NR
Standard-risk FISH / MRD+ (n=66); median TTP: 15 mos
High-risk FISH / MRD+ (n=19); median TTP: 12 mos
50403020100
100
80
60
40
20
0
Tim
e to
Pro
gres
sion
(%)
P <.001
Time From MRD Assessment (Mos)
P =.70
P =.02
Paiva B, et al. Blood. 2016;127:3165-3174.
Walker B, et al. J Clin Oncol. 2015;33:3911-3920.
ZFHX4
IRF4
EGFR1
Clinical impact of mutations in selected genes: Myeloma XI trial
Prognostic value of immune reconstitution in patients with persistent MRD
Time from MRD assessment (mos)
Tim
e-to
pro
gres
sion
(%)
P =.001
median TTP: NR
median TTP: 16m
PCA3
PCA1
normal PCs
median TTP: NR
clonal PCs
B-p
recu
rsor
sE
ryth
robl
asts
MRD+ with high normal PC recovery and favorable
immune profile
MRD–MRD+
Paiva B, et al. Blood. 2016;127:3165-3174As presented at ASH 2015.
Individual patient’ immune signatures
Single 8-color combination (CD45, CD138, CD38, CD56, CD27, CD19, CD117, CD81):Enumeration of 15 different BM cell populations
Patients with favorable immune profileare characterized by an increased compartment of mature B-cells
Need for integrated next-generation immunophenotypic and sequencing techniques for new concepts in risk
stratification toward precision medicine
Next-generation prognostication for precision medicine in multiple myeloma
PCA2
PCA150403020100
100
80
60
40
20
0Tim
e-to
pro
gres
sion
(%)
Time from MRD assessment (mos)
NK cells
B-cells
T-cells Prediction of outcomes based on big datasets
AgeECOGISSLDH…
Genetic landscape
Immune profiling
MRD monitoring
Prior treatment
Unsustained CR
Sustained CR
MRD positive
Which maintenance strategies are effective in patients with persistent MRD?
Maintenance?
80
100
60
20
40
0 P = .01
NGF+ (n=42),75% PFS: 10 mos
0 5 10 15 20 25 30
Next-generation MRD-negative patients:favorable outcome, but need to check for PB contamination
Flores-Montero J, et al. manuscript under review.NGF, next-generation flow.
Cell Population % Normal BMCells (Range) Case 1 Case 2
Mast cells 0.006% (0.002-0.03) 0.002% 0.0006%
Erythroblasts 6.4% (2-11.5) 8.01% 5.1%
CD19– nPC 0.05% (0.003-0.2) 0.004% 0.004%
CD19–/CD19+ nPC ratio 0.6% (0.08-1.1) 0.3% 0.08%
CD27+ B-cell precursors 0.08% (0.004-0.4) 0.0001% 0.003%
CD27– B-cell precursors 0.4% (0.05-2.2) 0.001% 0.01%
CD27+/CD27– B-cell precursor ratio 0.2% (0.04-1) 0.09% 0.3%
Mature B-cells 1.6% (0.6-3.5) 0.2% 0.1%
B-cell precursor/mature B-cell ratio 0.2% (0.03-1.1) 0.02% 0.1%
Myeloid precursors 1.8% (0.2-3.6) 0.3% 0.3%
Prog
ress
ion-
Free
Sur
viva
l (%
)
Time From MRD Assessment (Mos)
NGF– (n=37), 75% PFS: NR
InductionMRD–
HDT/ASCTMRD–
Diagnosis CRMRD+ 0.06%
ConsolidationMRD+ 0.003%
Myeloma is a patchy disease: need for continuous monitoring
Treatment stages
P = .02
PFS for patients withnegative PET-CT and negative MRD by flow
(47.7% of pts) vs otherspremaintenance
89.6%
54.5%
Moreau P, et al. Blood. 2015;126: abstract 395.
Kumar SK, et al (IMWG). Lancet Oncol. 2016;17:e328-e346.
IMWG Criteria for MRD in Multiple MyelomaIM
WG
MR
D N
egat
ivity
Crit
eria
(Req
uire
s C
R)
Sustained MRD-negative
MRD negative in the marrow (NGF or NGS) and by imaging as defined below, confirmed one yr apart. Subsequent evaluations can be used to further specify the duration of negativity (eg, MRD negative at 5 yrs, etc)
Imaging MRD-negative MRD negative as defined below (NGF or NGS) PLUS Disappearance of every area of increased tracer uptake found at baseline or a preceding PET/CT
Flow MRD-negative Absence of phenotypically aberrant clonal plasma cells by next-generation flow cytometry4 on bone marrow aspirates using the EuroFlow standard operation procedure for MRD detection in MM (or validated equivalent method) with a minimum sensitivity of 1 in 105 nucleated cells or higher
Sequencing MRD-negative
Absence of clonal plasma cells by next generation sequencing on bone marrow aspirates in which presence of a clone is defined as less than 2 identical sequencing reads obtained after DNA sequencing of bone marrow aspirates using the Lymphosight® platform (or validated equivalent method) with a minimum sensitivity of 1 in 105 nucleated cells or higher
myeloma.org/videos/ASH-Satellite-Symposium-2016
clinicaloptions.com/oncology
clinicaloptions.com/MyelomaTool
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