1. Value of MRD to Predict PFS in MM: Results From IFM/DFCI 2009
New Findings in Hematology: Independent Conference Coverage* of ASH 2015, December 5-8, 2015, Orlando, Florida
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
MRD, minimal residual disease.
This program is supported by educational grants from Amgen, Celgene Corporation, Incyte, Merck, Seattle Genetics, and Takeda Oncology.

2. IFM-DFCI 2009: Predictive Value of Minimal Residual Disease
Methods for assessing response to treatment in MM would benefit from improved sensitivity
Describing immunologic CR and molecular CR with 2-4 log reduction compared with current CR
MRD may represent important trial endpoint in MM[1]
Current study evaluated predictive value of MRD (assessed by FCM and NGS) for PFS[2]
FCM: requires fresh sample, 10-4 to 10-5 sensitivity
NGS: requires diagnostic sample (can be frozen), sensitivity
FCM, flow cytometry; MM, multiple myeloma; MRD, minimal residual disease; NGS, next-generation sequencing.
1. Martinez-Lopez J, et al. Blood. 2014;123: Avet-Loiseau H, et al. ASH Abstract 191.
Slide credit: clinicaloptions.com

3. IFM/DFCI 2009: Phase III Study Design
MRD
MRD
RVD*†
8 cycles * *
Pts 65 yrs of age or younger with symptomatic NDMM
(N = 700)
Lenalidomide
maintenance
12 mos
RVD*
3 cycles
MEL200
ASCT†
RVD*
2 cycles
consolidation
*RVD: bortezomib 1.3 mg/m2 IV on Days 1, 4, 8, 11 + lenalidomide 25 mg on Days dexamethasone 40 mg on Days 1, 8, 15.
†Included PBSC collection with cyclophosphamide 3 g/m2 + G-CSF after cycle 3.
ASCT, autologous stem cell transplantation; FCM, flow cytometry; MRD, minimal residual disease; MEL200, melphalan 200 mg/m2; NDMM, newly diagnosed multiple myeloma; NGS, next-generation sequencing; RVD, bortezomib, lenalidomide, dexamethasone; VGPR, very good PR.
Bone marrow MRD evaluation planned before and after maintenance for pts achieving ≥ VGPR in either arm
Primary objective: assess MRD by FCM
Secondary objective: assess MRD by NGS (n = 289)
Slide credit: clinicaloptions.com
Avet-Loiseau H, et al. ASH Abstract 191.

4. IFM-DFCI 2009: Evaluable Pt Characteristics
Median follow-up: 36 mos
Bone marrow MRD evaluation planned before and after maintenance for pts achieving ≥ VGPR
54% of pts had conventional CR
475 pts analyzed by flow
289 pts analyzed by molecular technique (NGS)
8% clone ID failure (92% applicability)
246 pts premaintenance: 87 negative, 80 low positive, 79 positive
179 pts postmaintenance: 86 negative, 52 low positive, 40 positive
MRD, minimal residual disease; NGS, next-generation sequencing; VGPR, very good PR.
Slide credit: clinicaloptions.com
Avet-Loiseau H, et al. ASH Abstract 191.

5. IFM-DFCI 2009: PFS by MRD Before Maintenance Therapy
MRD by FCM (10-4)
MRD by NGS (10-6)
1.0
0.8
0.6
0.4
0.2
1.0
0.8
0.6
0.4
0.2
P < .0001
P < .0001
Negative (n = 322) Positive (n = 153)
Negative (<10-6) (n = 87) Positive (n = 159) 6 12 18 24 30 36 42 48 6 12 18 24 30 36 42 48
Mos since randomization
Mos since randomization
51% of pts MRD negative by FCM were MRD positive by NGS, with similar trends in PFS by NGS MRD status
13 of 26 pts with t(4;14) achieved MRD negativity; none with del(17p)
Avet-Loiseau H, et al. ASH Abstract 191.
Reproduced with permission.
Slide credit: clinicaloptions.com

6. IFM-DFCI 2009: PFS by MRD After Maintenance Therapy
MRD by FCM (10-4)
MRD by NGS (10-6)
1.0
0.8
0.6
0.4
0.2
1.0
0.8
0.6
0.4
0.2
P < .004
P < .0001
Negative (n = 232) Positive (n = 78)
Negative (<10-6) (n = 86) Positive (n = 92) 6 12 18 24 30 36 42 48 6 12 18 24 30 36 42 48
Mos since randomization
Mos since randomization
38% of pts MRD negative by FCM were MRD positive by NGS, with similar trends in PFS by NGS MRD status
13 of 26 pts with t(4;14) achieved MRD negativity; none with del(17p)
Avet-Loiseau H, et al. ASH Abstract 191.
Reproduced with permission.
Slide credit: clinicaloptions.com

7. IFM-DFCI 2009: PFS by MRD in Pts Achieving sCR/CR
MRD (NGS) prior to maintenance tx
125 achieved sCR/CR; 55 pts available MRD
MRD (NGS) after maintenance tx
375 achieved sCR/CR; pts available MRD
1.0
0.8
0.6
0.4
0.2
1.0
0.8
0.6
0.4
0.2
83%
P < .0075
P < .0001
30%
Negative (<10-6) (n = 30) Positive (n = 25)
Negative (<10-6) (n = 80) Positive (n = 51) 6 12 18 24 30 36 42 48 6 12 18 24 30 36 42 48
Mos since randomization
Mos since randomization
Avet-Loiseau H, et al. ASH Abstract 191.
Reproduced with permission.
Slide credit: clinicaloptions.com

8. IFM-DFCI 2009: Conclusions
MRD-negative status significantly predictive of 3-yr PFS
NGS offers improved MRD sensitivity (< 10-6) over FCM and is feasible in most pts
MRD negativity at 10-6 level strongly predictive of 3-yr PFS, including pts who achieve CR and those with t(4;14) and in both treatment arms
Investigators concluded:
Sensitive MRD evaluation may identify pts cured of myeloma
Warrants further evaluation in clinical trials
FCM, flow cytometry; MRD, minimal residual disease; NGS, next-generation sequencing.
Slide credit: clinicaloptions.com
Avet-Loiseau H, et al. ASH Abstract 191.

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