Xavier Leleu Hôpital la Milétrie, PRC, CHU, Poitiers, France The case for IMids COMy Congress 21
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
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;32:142-52. 2. Moreau P, et al. N Engl J Med. 216;34:1621-34. 3. Richardson PG, et al. Blood. 214;123:1461-9. 4. Dimopoulos MA, et al. N Engl J Med. 216;35:1319-31. 5. Lonial S, et al. N Engl J Med. 215;33:621-31. 6. Dimopoulos MA, et al. Blood. 215;126:abstract 28.
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) 8 9 8 33 48 32 4 14 COMy Congress 21 28.6 2. 2.5 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;35:1319-31. 2. Stewart AK, et al. N Engl J Med. 215;32:142-52. 3. Lonial S, et al. N Engl J Med. 215;33:621-31. 4. Moreau P, et al. N Engl J Med. 216;34:1621-34.
Proportion surviving without progression Proportion surviving without progression Rd-based triplets Progression-free survival 1..8.6.4.2 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 1..8.6.4 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) 1.6.69 (.5.83) <.1 3 6 9 12 15 18 21 6 12 18 24 3 36 42 48 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;35:1319-31. 2. Stewart AK, et al. N Engl J Med. 215;32:142-52.
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 48 23.1 52 13.9..83 Standard 14 29.6 1 19.5.66.4 HR p value (one-sided) High 5 21.4 62 9..54 NR Standard 199 2.6 216 15.6.64 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;34:1621-34. 2. Avet-Loiseau H. Oral presentation at IMW 21, New Delhi, India.
MRD-negative rate (%) POLLUX: DRd vs Rd MRD-negative rate 5 4 3 2 1 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.
MRD-negative patients MRD-negative patients MRD at 1 5 by cytogenetic risk (NGS) per risk group (%) a 4 3 2 1 POLLUX p <.5 p <.1 3 18 1 High risk Standard risk (n = 28) (n = 3) (n = 133) (n = 113) 4 3 2 1 CASTOR 14 12 2 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.
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: http://clinicaltrials.gov/show/nct134928.
Lenalidomide backbone in the NDMM setting Rd + Proteasome inhibitor Or Monoclonal antibody COMy Congress 21 R as Continuous treatment
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.
Survival probability Lenalidomide maintenance: OS meta-analysis OS after a median follow-up of 8 months At risk, n Lenalidomide 1..8.6.4.2 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).1 1 2 3 4 5 6 8 9 1 1 1 12 Time (months) 86. (9.8 96.) 5% -yr OS 62% COMy Congress 21 65 58 555 59 44 431 385 282 2 95 2 1 Control 64 569 542 55 458 425 35 21 14 1 1 Attal M, et al. Presented at ASCO 216. J Clin Oncol. 216;34 Suppl:abstract 81.
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) 32 35.68 (.54.86) 233 229.83 (.63 1.1) 322 349.65 (.52.83) 283 255.91 (.69 1.19) 411 44.65 (.52.81) 113 9 1.4 (.2 1.51) 66 8.63 (.35 1.16) 32 339. (.54.9) 218 21.86 (.65 1.15) 14 146.48 (.31.5) 458 458.82 (.6 1.) Adverse-risk Yes 56 36 This 1.18 information (.66-2.1) is cytogenetics No not available for all 231 243.9 (.59-1.6) 3 trials included in CrCl after < 5 ml/min 33 25 the.3 analysis (.33-1.6) ASCT 5 ml/min 39 44.4 (.59-.92) COMy Congress 21.25.5 1 2 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 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 3 13 25 25 2 Range (min max) 18 51 61 55 49 Tx duration category, % COMy Congress 21 1 year 6 43 61 1 2 years 52 14 43 56 4 3 years 3 3 32 29 11 4 years 24 < 1 24 4 1 Attal M, et al. Presented at ASCO 216. J Clin Oncol. 216;34 Suppl:abstract 81.
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
Patients alive and progression-free (%) Overall PFS Significant improvement in PFS from 18 to 36 months, HR=.45 1 8 6 4 2 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<.1 3 6 9 12 15 18 21 24 2 3 33 36 39 42 45 48 51 54 5 6 63 66 Time since randomisation (months) No. of patients at risk: Lenalidomide Observation 85 694 1 584 65 54 611 413 512 353 444 293 369 24 33 22 265 16 228 132 24 18 169 86 143 64 118 48 9 4 6 25 43 2 2 1 1 3 11 2 4 2 1 1 CI, confidence interval; HR, hazard ratio
Proportion alive and progression-free Impact of maintenance by cytogenetic risk status 1..8.6.4.2 No. of patients at risk: Lenalidomide standard risk high risk Observation standard risk high risk 9 99 118 91 93 92 19 8 8 86 14 1 8 8 93 54 COMy Congress 21 83 2 83 4 81 6 69 39 4 58 5 36 Time since randomisation (months) 1 53 49 28 62 39 42 25 59 3 3 16 51 29 26 15 41 24 21 11 34 21 18 3 16 13 6 2 9 11 5 1 5 9 3 Lenalidomide standard risk high risk Observation standard risk high risk 3 6 9 12 15 18 21 24 2 3 33 36 39 42 45 48 51 54 5 6 63 13 1 6 3 8 2 1 4 1 1 Log-rank ⅔=51.492 p<.1 Outcome of high risk subgroup is clearly improved by the use of maintenance lenalidomide
Proportion alive and progression-free Impact of maintenance by MRD status 1..8.6.4.2 COMy Congress 21 3 6 9 12 15 18 21 24 2 3 33 36 39 42 45 48 51 Time since randomisation (months) Lenalidomide MRD-negative Lenalidomide MRD-positive Observation MRD-negative Observation MRD-positive Log-rank ⅔=55.5439 p<.1 Optimum outcomes are seen in the MRD-negative lenalidomide maintained group
Patients alive and progression-free (%) Duration of therapy Comparison <12 months, 12 24 months and >24 months HR [95% CI] <12 months (n=98) 26 [21, 4] 1 8 6 4 2 COMy Congress 21 12 24 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] 3 6 9 12 15 18 21 24 2 3 33 36 39 42 45 48 51 54 5 6 63 Time since randomisation (months) No. of patients at risk: <12 months 96 12 24 months 3 >24 months 91 3 81 3 66 3 54 3 4 29 31 28 2 28 18 23 12 2 12 2 9 16 6 13 5 9 6 2 4 4 1 3 3 1 3 1 1 1 1 1 1
Number of mutations Number of mutations Lenalidomide maintenance does not induce an excess of mutations 6 5 4 3 2 1 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 6 5 4 34 3 34 2 1 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)
Number of patients with mutation Mutational spectrum at presentation and relapse Frequency of mutations in lenalidomide maintenance patients at presentation and relapse 1 9 8 6 5 4 3 2 1 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
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) 1 8 6 4 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 21 8 6 4 PFS Median, months 4-y, % Continuous 26. 33 Rd Rd18 21. 14 MPT 21.9 13 33% 2 Hazard ratio: MPR-R vs MPR:.49; p<.1 MPR-R vs MP:.4; p<.1 5 1 15 2 25 3 35 4 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] 6 12 18 24 3 36 42 48 54 6 66 2 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;34:369-361.
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
Never give up! COMy Congress 21 Thank you for your attention