1. IMAJEM, a Substudy of IFM 2009: Prognostic Role of MRI and PET/CT in MM 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. This program is supported by educational grants from Amgen, Celgene Corporation, Incyte, Merck, Seattle Genetics, and Takeda Oncology.

2. MRI and PET/CT in MM: Background  Both MRI and PET/CT are imaging modalities used to detect bone lesions in pts with MM –Studies have suggested prognostic value for PFS and OS at diagnosis [1] and at follow-up [1,2]  Few trials have compared these modalities prospectively  Current IMAJEM study undertaken to compare MRI and PET/CT at diagnosis and in treatment and follow- up of intensive therapy for MMin IFM 2009 [3] 1. Bartel TB, et al. Blood. 2009;114;2068-2076. 2. Zamagni E, et al. Blood. 2011;118:5989-5995. 3. Moreau P, et al. ASH 2015. Abstract 395. Slide credit: clinicaloptions.comclinicaloptions.com

3. RVD* † 8 cycles IFM/DFCI 2009: Phase III Study Design Pts 65 yrs of age or younger with symptomatic NDMM with organ damage and measurable disease (N = 700) RVD* 3 cycles Lenalidomide maintenance 12 mos RVD* 2 cycles consolidation MEL200 ASCT † Avet-Loiseau H, et al. ASH 2015. Abstract 191. MRI or PET/CT at diagnosis MRI or PET/CT after 3 cycles of RVD MRI or PET/CT before maintenance Primary EndpointSecondary Endpoint Slide credit: clinicaloptions.comclinicaloptions.com  Phase III randomized study (N = 134 in IMAJEM analysis) *RVD: bortezomib 1.3 mg/m 2 IV on Days 1, 4, 8, 11 + lenalidomide 25 mg on Days 1-14 + dexamethasone 40 mg on Days 1, 8, 15. † Included PBSC collection with cyclophosphamide 3 g/m 2 + G-CSF after cycle 3.14

4. IMAJEM: Study Endpoints  Primary endpoint: diagnosis and staging –Comparing modalities in terms of number of bone lesions at diagnosis  Secondary endpoint: prognostic impact after 3 cycles of induction therapy and before maintenance –Determine relationship between PFS/OS and PET or MRI negativity  All MRIs and PET/CT scans centrally reviewed by 2 radiologists and 2 nuclear medicine physicians blinded to treatment arm Moreau P, et al. ASH 2015. Abstract 395. Slide credit: clinicaloptions.comclinicaloptions.com

5. IMAJEM: Baseline Characteristics  Median LDH elevated CharacteristicIMAJEM (N = 134) Median age, yrs (range)59 (37-65) Male sex, %62 Arm, %  Chemo only  Chemo + SCT 53 47 ISS stage, %  1  2  3 31 55 14 Median laboratory measurements (range)  Serum calcium, mmol/L  LDH, U/L  Hb, g/dL  Serum creatinine, µmol/L 2.28 (2.04-2.95) 211 (71-843) 10.9 (8.0-14.6) 78 (39-162) Cytogenetics, n  t(4;14) positive  del(17p) positive 6565 Moreau P, et al. ASH 2015. Abstract 395. Slide credit: clinicaloptions.comclinicaloptions.com

6. IMAJEM Primary Endpoint: Diagnosis and Staging  MRI of spine and pelvis and whole-body PET/CT equally effective in determining bone involvement at diagnosis (McNemar test =.94; P =.33) Response, n (%)MRIPET/CT Positivity127 (94.7)122 (91)  Focal lesions 46 (34)44* (33)  Homogeneous diffuse infiltration 41 (31)12 (9)  Combined diffuse infiltration + focal lesions 35 (26)66 (49)  Variegation + inhomogeneous BM 5 (4)NR  Extramedullary disease NR10 (7.5) Normal bone7 (5)12 (9) Moreau P, et al. ASH 2015. Abstract 395. *Median number of focal lesions = 3 (range: 0 to > 10); median SUV max = 4.1 (range: 1.5-28.4). Slide credit: clinicaloptions.comclinicaloptions.com

7. IMAJEM Secondary Endpoint: Prognostic Impact After 3 Induction Cycles  Negative MRI (3% of pts) not predictive of survival  Negative PET/CT (32% of pts) associated with improved PFS, not OS Moreau P, et al. ASH 2015. Abstract 395. Reproduced with permission. Probability of PFS MRI neg MRI pos 1.0 0.8 0.6 0.4 0.2 0.0 P =.29 61.6% 0102030 Probability of OS MRI neg MRI pos 1.0 0.8 0.6 0.4 0.2 0.0 P =.61 86.1% 0102030 40 Probability of PFS PET/CT neg PET/CT pos 1.0 0.8 0.6 0.4 0.2 0.0 P =.04 54.8% 0102030 Probability of OS PET/CT neg PET/CT pos 1.0 0.8 0.6 0.4 0.2 P =.12 81.8% 0102030 40 78.7% 92.8% 0.0 Slide credit: clinicaloptions.comclinicaloptions.com

8. IMAJEM Secondary Endpoint: Prognostic Impact Before Maintenance  Negative MRI (11% of pts) not predictive of survival  Negative PET/CT (62% of pts) associated with improved PFS, OS Slide credit: clinicaloptions.comclinicaloptions.com Probability of PFS MRI neg MRI pos 1.0 0.8 0.6 0.4 0.2 0.0 P =.30 60.7% 0102030 Probability of OS MRI neg MRI pos 1.0 0.8 0.6 0.4 0.2 0.0 P =.30 85.1% 0102030 40 Probability of PFS PET/CT neg PET/CT pos 1.0 0.8 0.6 0.4 0.2 0.0 P < 0.001 51.6% 0102030 Probability of OS PET/CT neg PET/CT pos 1.0 0.8 0.6 0.4 0.2 P =.003 69.9% 0102030 40 69% 94.6% 0.0 83.9% Moreau P, et al. ASH 2015. Abstract 395. Reproduced with permission.

9. IMAJEM: Univariate Analysis of Prognostic Value for PFS, OS  Univariate analysis performed with variables including: sex, age, calcium, creatinine, ISS score, response to induction chemotherapy, premaintenance response to therapy, cytogenetics, MRI after 3 cycles of chemotherapy, PET/CT after 3 cycles of chemotherapy, MRI before maintenance, PET/CT before maintenance Confirmed Prognostic FactorsCorrelation P Value PFS analysis  PET/CT after 3 cycles  PET/CT before maintenance  Response (≥ VGPR) after 3 cycles.04 <.001.04 OS analysis  PET/CT before maintenance.003 Moreau P, et al. ASH 2015. Abstract 395. Slide credit: clinicaloptions.comclinicaloptions.com

10. IMAJEM: Premaintenance PET/CT as Prognostic Factor for Response  PET/CT normalization before maintenance prognostic for efficacy endpoints in both arms Premaintenance PET/CT NegativeCorrelation P Value PFS with RVD alone  Adjusted based on other prognostic factors  Univariate log-rank.009.027 PFS with RVD + ASCT  Adjusted based on other prognostic factors  Univariate log-rank.01 OS with RVD + ASCT  Adjusted based on other prognostic factors  Univariate log-rank.008 <.001 Moreau P, et al. ASH 2015. Abstract 395. Slide credit: clinicaloptions.comclinicaloptions.com

11. IMAJEM: Premaintenance PET/CT and MRD Negativity as Predictor for PFS  Additional data assessed MRD status (by flow cytometry) on 86 of the 134 pts in this study [1] 1. Avet-Loiseau H, et al. ASH 2015. Abstract 191. 2. Moreau P, et al. ASH 2015. Abstract 395. Reproduced with permission. Slide credit: clinicaloptions.comclinicaloptions.com PET/CT PositivePET/CT Negative MRD positive1120 MRD negative1441 Fisher exact test, P =.33; McNemar test, P =.39 PET/CT/MRD neg Others Probability of PFS 1.0 0.8 0.6 0.4 0.2 0.0 P =.02 54.5% 89.6% 35051015202530

12. IMAJEM: Conclusions  Assessment of MRI and PET/CT from both arms (RVD with or without ASCT) of the IFM 2009 trial suggest: –PET/CT and MRI both effective in detecting bone lesions at diagnosis –PET/CT negativity after 3 cycles of chemotherapy and before maintenance is prognostic for PFS –PET/CT negativity before maintenance is prognostic for OS –PET/CT and flow cytometry can be used concurrently to successfully evaluate MRD Moreau P, et al. ASH 2015. Abstract 395. Slide credit: clinicaloptions.comclinicaloptions.com

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