Study Objectives: GMMG MM5

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2 Study Objectives: GMMG MM5 1.) Demonstration of non-inferiority of VCD induction therapy compared to PAd induction therapy with respect to response rate (very good partial remission or better; response criteria of the International Myeloma Working Group, IMWG). 2.) Determination of the best of four treatment strategies with respect to progressionfree survival (PFS). The four treatment strategies are defined by PAd vs. VCD induction treatment, standard intensification therapy, lenalidomide consolidation and maintenance treatment with lenalidomide for 2 years vs. lenalidomide until CR.

3 GMMG MM5: Study Design

4 GMMG MM5: Induction Therapy VCD is less toxic and equally effective compared to PAd Peripheral neuropathy is reduced upon subcutaneous versus intravenous administration of bortezomib Mai EK et al., Leukemia, 2015 I Merz M et al., 2015, Haematologica

5 Lenalidomide Maintenance EMA and FDA have approved lenalidomide maintenance therapy for newlydiagnosed, transplant-eligible MM (initial dose 10mg, up to 15mg) Continuous treatment until progression or unacceptable toxicity Meta-analysis of three independent phase III trials demonstrated improved OS MRC Myeloma XI: Tx with LEN maintenance therapy until progression resulted in a highly significant improvement in PFS and OS for pts of all ages with NDMM irrespective of cytogenetic risk: Results of the myeloma XI trial (Graham Jackson et al. ASH 2017 Abstract 436, Sunday, December 10, 2017: 12:45 oral presentation) The GMMG-MM5 trial is the first phase III IIT investigating response-adapted lenalidomide maintenance duration

6 GMMG MM5:Primary Endpoint: Progression-Free Survival Determination of the best of four treatment strategies with respect to PFS Comparison of two different IT regimen and maintenance strategies A1: PAd + LEN MT for 2 years = PAd-LEN-2Y B1: PAd + LEN MT until CR = PAd-LEN-CR A2: VCD + LEN MT for 2 years = VCD-LEN-2Y B2: VCD + LEN MT until CR= VCD-LEN-CR

7 GMMG MM5: Consort diagram Randomized (n=504) PAd-LEN-2Y (Arm A1) (ITT n=125; Safety n=126) PAd-LEN-CR (Arm B1) (ITT n=126; Safety n=122) VCD-LEN-2Y (Arm A2) (ITT n=126; Safety n=126) VCD-LEN-CR (Arm B2) (ITT n=125; Safety n=124) Stem cell mobilisation (n=113, 90.4%) Stem cell mobilisation (n=109, 86.5%) Stem cell mobilisation (n=116, 92.1%) Stem cell mobilisation (n=112, 89.6%) HDM / ASCT single (n=84, 67.2%) tandem (n=25, 20.0%) HDM / ASCT single (n=73, 57.9%) tandem (n=27, 21.4%) HDM / ASCT single (n=79, 62.7%) tandem (n=35, 27.8%) HDM / ASCT single (n=72, 57.6%) tandem (n=36, 28.8%) LEN consolidation (n=101, 80.8%) LEN consolidation (n=93, 73.8%) LEN consolidation (n=104, 82.5%) LEN consolidation (n=101, 80.8%) LEN maintenance (n=93, 74.4%) LEN maintenance (n=80, 63.5%) no LEN because of CR: after consolidation: n=31 during maintenance: n=15 LEN maintenance (n=95, 75.4%) LEN maintenance (n=92, 73.6%) no LEN because of CR: after consolidation: n=29 during maintenance: n=13 Completion of LEN maintenance (2 years) or observation (n=68, 54.4%) Completion of LEN maintenance (2 years), observation or surveillance (CR only) (n=55, 43.7%) Completion of LEN maintenance (2 years) or observation (n=63, 50.0%) Completion of LEN maintenance (2 years), observation or surveillance (CR only) (n=54, 43.2%)

8 Results GMMG MM5: PFS

9 Results GMMG MM5: PFS 321 PFS events were reported Median follow up of 60.1 months There was no significant PFS difference between the four treatment arms The assumed 3-year PFS rates (PAd-LEN-2Y: 58%, PAd-LEN-CR: 49%, VCD-LEN-2Y: 54%, VCD-LEN-CR: 49%) lie below the assumed ones (55%, 65% and 75%) The observed effects in PFS (most extreme HR=1.2) lie below the assumed ones (HR of 1.5 and 2.1)

10 Results GMMG MM5: OS

11 Results GMMG MM5: OS Death of n=160 patients is reported 3-year OS rates: 82.9 vs vs vs. 77.1% in the arms A1, A2, B1 and B2, respectively Significant difference in OS between the four treatment arms (p=0.02) Pairwise comparison of treatment arms revealed an inferior OS in arm B1 (PAd-LEN-CR) versus arm A1 (PAd-LEN-2Y)

12 PFS + OS Pooled Maintenance Strategies ITT

13 GMMG MM5: Landmark (after cons.) PFS + OS

14 CR: Landmark (after cons.) PFS + OS

15 Non-CR: Landmark (after cons.) PFS + OS

16 Adverse cytogenetics PFS + OS Adverse cytogenetics are defined as either t(4;14), del17p13 and/or gain1q21 (> 3 copies)

17 Revised International Staging System (R-ISS) PFS + OS

18 Results GMMG MM5: Toxicities Overall toxicity is higher in the LEN-2Y compared to LEN-CR arms, this is based on an increased toxicity during maintenance within the LEN-2Y arms, mainly infections (upper airways, pulmonary), no toxic death during maintenance.

19 Results GMMG MM5: Multivariate Model Significant impact of maintenance strategy on OS (study arms B1+B2 vs. A1). ISS and adverse CA are the strongest predictors for PFS and OS.

20 Circulating Tumor Cells as a Surrogate Marker Results I. CTCs as surrogate for BM MRD assessment Presence of CTCs predicts MRD-positivity in BM with high specificity. Scatter plot for correlation between the number of tumor cells in BM vs. the number of circulation tumor cells shades of gray: cut off 10-5, cut off St. Huhn, ASH 2017,Poster Monday, Poster 4359

21 Circulating Tumor Cells as a Surrogate Marker Results II. Prognostic value of CTCs assessment. CTCs after IT are associated with poor PFS MRD - positivity & CTCs after ASCT are associated with poor OS Kaplan-Meier plots and corresponding p-values for CTC/MRD - negativity and OS/PFS. IT induction therapy, ASCT high dose Melphalan and autologous stem cell transplantation St. Huhn, ASH 2017, Poster Monday, Poster 4359

22 Conclusions I First multicenter phase III IIT reporting on response-adapted LEN maintenance strategy. OS, but no PFS, difference was observed between PAd-LEN-2Y (arm A1) and PAd-LEN-CR (arm B1, p=0.02). OS benefit for LEN-2Y strategy on multivariate analyses. Maintenance strategies in CR patients appear to drive this difference. PFS benefit of LEN maintenance among CR patients (HR=1.84, p=0.02).

23 Conclusions II LEN maintenance is associated with increased manageable toxicity (leucopenia, thrombosis and infections), no toxic death during maintenance occurred. For cytogenetic high-risk patients there was a trend for better PFS in Len-2 years arms vs Len-CR arms in landmark analysis since start of maintenance. Circulating tumor cells after induction and intensification (ABSCT) are predictive for outcome. Predictive value of MRD in bone marrow (Flow) in terms of outcome is under evaluation. Results of the GMMG MM5 trial suggest that LEN MT should be applied beyond the achievement of a CR.

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25 Acknowledgements GMMG Germany and all participating sites GMMG Heidelberg Dr. Uta Bertsch, Dr. Elias K. Mai Biostatistics DKFZ Heidelberg Dr. Christina Kunz, Thomas Hielscher KKS Heidelberg Dr. Steffen Luntz, Dr. Baerbel Schurich