COMy Congress The case for IMids. Xavier Leleu. Hôpital la Milétrie, PRC, CHU, Poitiers, France

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1 Xavier Leleu Hôpital la Milétrie, PRC, CHU, Poitiers, France The case for IMids COMy Congress 21

2 Disclosures Grants/research support: Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millennium/Takeda, Novartis, Sanofi Speakers bureau/honoraria: Amgen, Bristol-Myers Squibb, Celgene, Janssen, Novartis Consulting fees: Amgen, Bristol-Myers Squibb, Celgene, Janssen COMy Congress 21

3 Rd backbone in the Early RRMM setting Rd + Proteasome inhibitor Carfilzomib 1 Ixazomib 2 Bortezomib 3 Rd + Monoclonal antibody 4-6 Anti-CD38 (daratumumab, isatuximab) Anti-SLAMF (elotuzumab) Triplet improves median PFS 6 months to? years High risk improves MRD becomes a new objective COMy Congress 21 MRD, minimal residual disease; PFS, progression-free survival. 1. Stewart AK, et al. N Engl J Med. 215;32: Moreau P, et al. N Engl J Med. 216;34: Richardson PG, et al. Blood. 214;123: Dimopoulos MA, et al. N Engl J Med. 216;35: Lonial S, et al. N Engl J Med. 215;33: Dimopoulos MA, et al. Blood. 215;126:abstract 28.

4 Studies evaluating Rd-based triplets PFS HR (95% CI) POLLUX DRd vs Rd 1.3 (.2.52) ORR, % 93 VGPR, % 6 CR, % 43 Duration of response, mo NE ASPIRE KRd vs Rd 2.69 (.5.83) ELOQUENT-2 ERd vs Rd 3.3 (.6.89) TOURMALINE- MM1 IRd vs Rd 4.4 (.59.94) COMy Congress OS HR (95% CI).64 (.4 1.1).9 (.63.99). (.61.9) NE Direct comparisons across trials is not intended and should not be inferred. CI, confidence interval; CR, complete response; HR, hazard ratio; NE, not estimable; OS, overall survival; VGPR, very good partial response. 1. Dimopoulos MA, et al. N Engl J Med. 216;35: Stewart AK, et al. N Engl J Med. 215;32: Lonial S, et al. N Engl J Med. 215;33: Moreau P, et al. N Engl J Med. 216;34:

5 Proportion surviving without progression Proportion surviving without progression Rd-based triplets Progression-free survival POLLUX 1 Anti-CD38 + LEN + Dex HR.3 (95% CI.2.52) p <.1 12-month PFS 83% 6% 18-month PFS 8% 52% Rd Median PFS: 18.4 mo DRd COMy Congress 21.2 ASPIRE 2 PI + LEN + Dex Median PFS, mo HR (KRd/Rd) (95% CI) p value (one-sided) KRd (n = 396) 26.3 Rd (n = 396) (.5.83) < Months Months Direct comparisons across trials is not intended and should not be inferred. Dex, dexamethasone; LEN, lenalidomide; PI, proteasome inhibitor. 1. Dimopoulos MA, et al. N Engl J Med. 216;35: Stewart AK, et al. N Engl J Med. 215;32:

6 Rd triplets PFS by cytogenetic group Tourmaline- MM1 (IRd vs Rd) 1 Risk group by FISH ASPIRE KRd (n = 396) Rd (n = 396) (KRd vs Rd) 2 N Median (mo) N Median (mo) Risk group by FISH IRd (n = 36) Rd (n = 362) N Median (mo) N Median (mo) HR p value (one-sided) High Standard HR p value (one-sided) High NR Standard a NR COMy Congress 21 a p <.5 for comparison between regimens. b Alone or in combination with t(4;14) or t(14;16). Data on patients with t(14:16) alone not included due to small numbers (n = ). Direct comparisons across trials is not intended and should not be inferred. FISH, fluorescence in situ hybridization; NR, not reported; ORR, overall response rate. 1. Moreau P, et al. N Engl J Med. 216;34: Avet-Loiseau H. Oral presentation at IMW 21, New Delhi, India.

7 MRD-negative rate (%) POLLUX: DRd vs Rd MRD-negative rate p <.1 3% 8% p <.1 23% COMy Congress 21 5% p <.1 1% 2% DRd Rd MRD-negative (1 4 ) MRD-negative (1 5 ) MRD-negative (1 6 ) Response-evaluable set. Assessed by next generation sequencing (NGS) in bone marrow. Avet-Loiseau H. Oral presentation at IMW 21. New Delhi, India.

8 MRD-negative patients MRD-negative patients MRD at 1 5 by cytogenetic risk (NGS) per risk group (%) a POLLUX p <.5 p < High risk Standard risk (n = 28) (n = 3) (n = 133) (n = 113) CASTOR High risk (n = 44) (n = 51) Standard risk (n = 123) (n = 135) DRd (1% high risk b ) Rd (25% high risk b ) DVd (26% high risk b ) Vd (2% high risk b ) per risk group (%) a COMy Congress 21 p <.5 p <.5 No high-risk MRD-negative patients have progressed or converted to MRD-positive High risk = any of t(4;14), t(14;16), del1p Standard risk = conclusive absence of all 3 markers p values calculated using likelihood-ratio chi-square test. a Percentage of patients within a given risk group and treatment arm. b Percentage of patients within a given treatment arm within the biomarker-evaluable population. DVd, daratumumab-bortezomib-dexamethasone. Avet-Loiseau H, et al. Presented at ASH 216. Blood. 216;128:abstract 246.

9 N = 82 (planned) Randomization Pomalidomide + bortezomib + LoDEX in RRMM MM- phase 3 trial design Primary endpoint: PFS Key secondary endpoints: 21-day OS, cycles ORR, DoR, safety POM: 4 mg D1 14 Bort: a 1.3 mg/m 2 LoDex: b,c 2 mg Bort: a 1.3 mg/m 2 Dex: b,c 2 mg Ongoing treatment until PD COMy Congress 21 Long-term follow-up for OS until 5 years after initial treatment Primary endpoint: PFS Key secondary endpoints: OS, ORR, DoR, safety a Bort: cycles 1 8: D1, 4, 8, 11; cycles 9 onwards: D1, 8, 21. b Dex: 1 mg if patient is > 5 years old. c Dex: cycles 1 8: D1 2, 4 5, 8 9, 11 12; cycles 9 onwards: D1 2, 8 9. LoDex, low-dose dexamethasone; PD, progressive disease; POM, pomalidomide. ClinicalTrials.gov. Available from:

10 Lenalidomide backbone in the NDMM setting Rd + Proteasome inhibitor Or Monoclonal antibody COMy Congress 21 R as Continuous treatment

11 Lenalidomide maintenance: OS meta-analysis Studies included CALGB 114 (accrual 8/25 11/29) Induction ASCT 1:1 randomization No evidence of PD PLACEBO (n = 229) LEN (n = 231) IFM 25-2 (accrual 6/26 8/28) Induction ASCT 1:1 randomization No evidence of PD PLACEBO (n = 3) LEN: 2 courses LEN (n = 3) No treatment (n = 68) GIMEMA (RV-MM-PI-29) (accrual 11/2 /29) ASCT COMy Congress 21 2 x 2 design LEN + DEX x 4 Induction LEN (n = 6) MPR: 6 courses No Tx LEN Crossover before PD allowed Continued treatment No crossover before PD allowed Continued treatment Continued treatment Continued treatment ALL treatment discontinued Jan 211 Dex, dexamethasone; MPR, melphalan-prednisone-lenalidomide; Tx, treatment. Attal M, et al. Presented at ASCO 216. J Clin Oncol. 216;34 Suppl:abstract 81.

12 Survival probability Lenalidomide maintenance: OS meta-analysis OS after a median follow-up of 8 months At risk, n Lenalidomide Lenalidomide reduces the risk of death by 26% N = 1,29 Lenalidomide Control Median OS (95% CI), mo HR (95% CI) p value NE (NE NE).4 (.62.89) Time (months) 86. ( ) 5% -yr OS 62% COMy Congress Control Attal M, et al. Presented at ASCO 216. J Clin Oncol. 216;34 Suppl:abstract 81.

13 13 Lenalidomide maintenance: OS meta-analysis Subgroup analysis Age Sex ISS stage Response after ASCT Prior induction therapy < 6 y 6 y Male Female I or II III CR CR/VGPR PR/SD/PD LEN Non-LEN LEN Control HR (95% CI) (.54.86) ( ) (.52.83) ( ) (.52.81) ( ) ( ) (.54.9) ( ) (.31.5) (.6 1.) Adverse-risk Yes This 1.18 information ( ) is cytogenetics No not available for all ( ) 3 trials included in CrCl after < 5 ml/min the.3 analysis ( ) ASCT 5 ml/min ( ) COMy Congress HR Favours LEN Favours control CrCl, creatinine clearance; ISS, international staging system; PR, partial response; SD, stable disease; VGPR, very good partial response. Attal M, et al. Presented at ASCO 216. J Clin Oncol. 216;34 Suppl:abstract 81.

14 14 Lenalidomide maintenance Duration of treatment LEN (n = 224) CALGB 114 IFM 25-2 Placebo (n = 221) Placebo up to crossover (n = 221) LEN after crossover (n = 6) LEN (n = 36) Placebo (n = 32) Mean Tx duration, mo Range (min max) Tx duration category, % COMy Congress 21 1 year years years years 24 < Attal M, et al. Presented at ASCO 216. J Clin Oncol. 216;34 Suppl:abstract 81.

15 Myeloma XI Induction NDMM Treated on Myeloma XI induction protocols N=1551 (TE=828; TNE=23) Median follow-up: 2 months (IQR 13 43) Maintenance Lenalidomide 1 mg/day, days 1 21/28 Observation Exclusion criteria Failure to respond to lenalidomide as induction IMiD, or development of PD Previous or concurrent active malignancies IQR, interquartile range; NDMM, newly diagnosed multiple myeloma; PD, progressive disease R 1:1 COMy Congress 21

16 Patients alive and progression-free (%) Overall PFS Significant improvement in PFS from 18 to 36 months, HR= COMy Congress 21 Median PFS, months [95% CI] Lenalidomide (n=85) 36 [31, 39] Observation (n=694) 18 [16, 2] HR=.45; 95% CI.39,.52 Log-rank p< Time since randomisation (months) No. of patients at risk: Lenalidomide Observation CI, confidence interval; HR, hazard ratio

17 Proportion alive and progression-free Impact of maintenance by cytogenetic risk status No. of patients at risk: Lenalidomide standard risk high risk Observation standard risk high risk COMy Congress Time since randomisation (months) Lenalidomide standard risk high risk Observation standard risk high risk Log-rank ⅔= p<.1 Outcome of high risk subgroup is clearly improved by the use of maintenance lenalidomide

18 Proportion alive and progression-free Impact of maintenance by MRD status COMy Congress Time since randomisation (months) Lenalidomide MRD-negative Lenalidomide MRD-positive Observation MRD-negative Observation MRD-positive Log-rank ⅔= p<.1 Optimum outcomes are seen in the MRD-negative lenalidomide maintained group

19 Patients alive and progression-free (%) Duration of therapy Comparison <12 months, months and >24 months HR [95% CI] <12 months (n=98) 26 [21, 4] COMy Congress months (n=3) 39 [32, ] >24 months (n=) 6 [38, 6] 12 24m vs. <12m HR=.39 95% CI [.21,.2] >24m vs. <12m HR=.13 95% CI [.8,.58] Time since randomisation (months) No. of patients at risk: <12 months months 3 >24 months

20 Number of mutations Number of mutations Lenalidomide maintenance does not induce an excess of mutations Whole exosome study of paired presentation relapse samples; 35 treated with lenalidomide maintenance and 35 observation. Mutational load at presentation 3 p=.5 Lenalidomide Observation Maintenance randomisation COMy Congress 21 Mutational load at relapse Lenalidomide p=.22 Maintenance randomisation 44 Observation The median number of mutations at presentation was similar in the two groups (3 lenalidomide versus 34 observation; p=.5) The median number of mutations at relapse was reduced in patients randomised to lenalidomide maintenance versus observation only (34 lenalidomide versus 44 observation; p=.22)

21 Number of patients with mutation Mutational spectrum at presentation and relapse Frequency of mutations in lenalidomide maintenance patients at presentation and relapse COMy Congress 21 Presentation only Relapse only Presentation and relapse Total Mutation No specific mutational pattern was seen at relapse that differs between the two groups

22 Patients (%) Patients (%) PD or unacceptable toxicity Lenalidomide 25 mg/day ± Dex RANDOMISATION 1:1:1 PD, OS and subsequent anti-mm Tx Transplant non-eligible MM-15 1 MM-2 2,3 N = 459 Newly diagnosed Transplantineligible Stratified by age (65-5 vs >5 years) and disease stage (ISS I/II vs III) R 1:1:1 MPR-R (n=152) M:.18 mg/kg, days 1 4 P: 2 mg/kg, days 1 4 R: 1 mg/day po, days 1 21 MPR-R (n =53) M, P & R as in MPR-R MP (n=154) M & P as in MPR-R Placebo: days 1 21 Cycles (28-day) 1 9 Double-blind treatment PFS Maintenance Lenalidomide 1 mg/day days 1 21 Placebo Placebo Cycles 1+ Openlabel Median, months MPR-R 31. MPR 14 MP 13 Continuous Rd until PD or unacceptable toxicity (n=535) Arm A Lenalidomide 25 mg days 1-21/28 Dexamethasone 4 mg days 1, 8, 15 & 22/28 Arm B Arm C Rd18 (Rd for 18 cycles [2 weeks])* (n=541) Lenalidomide 25 mg days 1-21/28 Dexamethasone 4 mg days 1, 8, 15 & 22/28 MPT for 12 cycles (2 weeks)* (n=54) Melphalan.25 mg/kg days 1 4/42 Prednisone 2 mg/kg days 1 4/42 Thalidomide 2 mg days 1 42/42 Patients > 5 years: dexamethasone 2 mg days 1, 8, 15 & 22/28; melphalan.2 mg/kg days 1-4/42; thalidomide 1 mg days 1-42/42 1 COMy Congress PFS Median, months 4-y, % Continuous Rd Rd MPT % 2 Hazard ratio: MPR-R vs MPR:.49; p<.1 MPR-R vs MP:.4; p< Time (months) *Treatment continued until either completion of specified number of cycles or occurrence of PD or unacceptable toxicity, whichever came first ISS, International Staging System; OS, overall survival; PD, progressive disease 2 Hazard ratio (95% CI): Continuous Rd vs MPT:.69 [.59,.8] Continuous Rd vs Rd18:.1 [.61,.83] Rd18 vs MPT:.99 [.86, 1.14] Time (months) 14% 13% 1. Palumbo A,et al. N Engl J Med 212;366:159-69; 2. Benboubker L, et al. N Engl J Med 214;31:96-1; 3. Hulin C, et al. J Clin Oncol 216;34:

23 Myeloma a Chronic disease for Elderly Regimens Ird vs Rd ElotuzumabRd vs Rd DaratumumabRd vs Rd CRd MRC Vrd vs Rd KRd vs VRd COMy Congress 21 Phase 3 trials Tourmaline MM2 Eloquent1 MAIA MRCXI SWOG

24 Never give up! COMy Congress 21 Thank you for your attention