ENDEAVOR – Overall Survival Analysis 49c19f2e 0bcd 42a1 B1b2 E15eb5dedcb6
2018-06-18
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6/18/2018 Optimizing Therapy of Relapsed/Refractory Multiple Myeloma Noopur Raje, MD Director, Center for Multiple Myeloma MGH Cancer Center Professor of Medicine Harvard Medical School Disclosures • Consultant /Advisory Board: Celgene, Millenium Takeda, Amgen-Onyx, Novartis, Janssen, BMS, Merck, Bluebird • Research Funding: Astra Zeneca • Steering Committee: Amgen, Roche Myeloma: Scope of the Problem • Median time to first relapse with current therapies: 3-4 yrs 1.0 0.9 0.8 OS (%) 0.7 2006-2010 0.6 > 100,000 pts living with myeloma 0.5 0.4 2001-2005 0.3 0.2 0.1 0 0 1 2 3 Yrs 4 5 6 Kumar SK, et al. Leukemia. 2014;28:1122-1128. 1 6/18/2018 12 100 10 80 8 Pts (%) Median Response Duration (Mos) Confronting Disease Relapse in Myeloma 6 4 OS EFS Median, Mos (Range) 9 (7-11) 5 (4-6) Events, n/N 170/286 217/286 60 40 20 2 0 0 First Second Third Fourth Fifth Treatment Regimen Sixth 0 12 24 36 48 60 Mos Kumar SK, et al. Mayo Clin Proc. 2004;79:867-874. Kumar SK, et al. Leukemia. 2012;26:149-157. Current estimates for patients refractory to both IMiDs and PIs From 1st relapse From PI and IMiD resistance Kumar et al, Leukemia 2017 Clonal Evolution with Progression Mutation Load by Disease Stage Altered Genes per Patient 2 6/18/2018 Targeting the drivers- Myc: IMiDs Schaffer et al, Nature. 454. 226-31 Stewart. Science 2014;343:256-257; Lu et al Science 2014;343:305-309; Kronke et al. Science 2014;343:301-305 Targeting the Proteasome Gillmore, Cancer Cell, 12(2), p95–97, 14 August 2007; Anderson Clin Cancer Res 2016;22:5419-5427 Rational combination strategies in relapsed, refractory MM 3rd generation IMiDs (POM) 2nd, 3rd generation PI’s (CFLZ, IXA) + MoAbs Lonial S, Mitsiades CS, Richardson PG. Clin Cancer Res 2011;17:1264-77. 3 6/18/2018 Selected phase III trials in relapsed disease No. prior lines Name of trial 1-3 ENDEAVOR TOURMALINE-MM1 1-3 ELOQUENT-2 1-3 1-3 ASPIRE 1-3 PANORAMA 1 ≥2§ NIMBUS (MM-003) ≥1 CASTOR ≥1 POLLUX Arm N PFS (months) ORR ≥VGPR ≥CR Kd 464 18.7 77% 54% 13% Vd 465 9.4 63% 29% 6% IRd 360 20.6 78% 48% 12% Rd 362 14.7 72% 39% 7% Elo-Rd 321 19.4 79% 33% 4% Rd 325 14.9 66% 28% 7% KRd 396 26.3 87% 70% 32% Rd 396 17.6 67% 40% 9% Pano-Vd 387 11.99 61% Vd 381 8.08 55% Pd 302 4.0 31% 6% 1% D 153 1.9 10% 1% 0% Vd-dara 251 NE 82.9% 59.2% 19.2% Vd 247 7.2 63.2% 29.1% 9% Rd-dara 286 NE 93% 76% 43% Rd 283 18.4 76% 44% 19% 11% 6% Arm A: Once-weekly carfilzomib + dex N = 478 Relapsed and Refractory MM • 2-3 prior lines • Prior exposure to IMiD & PI • PS 0-1 (30 min infusion of K) Carfilzomib 20 mg/m 2 IV D1 (Cycle 1) Carfilzomib 70 mg/m 2 IV D8, 15 (Cycle 1), D1, 8, 15 (Cycle 2+) Dexamethasone 40 mg IV/PO D1, 8, 15 (All cycles) Dexamethasone 40 mg IV/PO D22 (Cycles 1-9 only) 28-day cycles Arm B: Twice-weekly carfilzomib + dex (10 min infusion of K) Carfilzomib 20 D1, 2 (Cycle 1) Carfilzomib 27 mg/m 2 IV D8, 9, 15, 16 (Cycle 1), D1, 2, 8, 9, 15, 16 (Cycle 2+) Dexamethasone 40 mg IV/PO D1, 8, 15 (All cycles) Dexamethasone 40 mg IV/PO D22 (Cycles 1-9 only) Stratification: mg/m 2 IV • ISS stage • Refractory to bortezomib • Age (<65 vs. ≥65) Long-term Follow-up for Survival 1:1 Randomization • Follow-up for Disease Status until Confirmed PD A.R.R.O.W. Study Design . Proportion Surviving Without Progression Primary Endpoint: Progression-Free Survival Assessed by Computational Algorithm Based on IMWG-URC 1.0 0.8 ++ + + ++ ++ ++ ++ 0.6 Kd Twice-weekly Kd Once-weekly ++ + ++++++++ ++ + + ++ + 0.4 0.2 0.0 ++++ +++++++++++ ++++++++++ + ++ +++ ++ +++ ++ +++ +++ + ++ + ++++ +++ + ++ ++++ +++ + +++ +++ + ++ ++++ ++ + +++ + Twice-weekly Kd 20/27 mg/m Progression/Death,n (%) Median PFS, months HR(Kd 20/70/Kd 20/27)(95% CI) p-value (1-sided) 0 3 Number of Subjects at Risk: Kd 20/27 238 164 Kd 20/70 240 178 Once-weekly 2 Kd 20/70 mg/m (N=238) ----------148 (62.2%) 7.6 0.693 (0.544, 0.883) 0.0014 6 119 145 2 (N=240) ----------126 (52.5%) 11.2 9 12 15 Months from Randomization 86 114 41 69 15 24 18 21 4 5 0 0 4 6/18/2018 What about Len refractory patients? Len-refractory RRMM Available Efficacy Data on Len-refractory RRMM Patients Trial/Regimen Analysis set N PFS ORR MRD neg. rate at 10-5 CASTOR3 D-Vd vs Vd Len-refractory at last prior line of therapy D-Vd: n = 45 Vd: n = 60 Median: 9.3 mo vs 4.4 mo HR: 0.36; 95% CI, 0.21-0.63; P = 0.0002 18-mo PFS rate: 34% vs 2% 81% vs 50% P = 0.0021 9% vs 0% P = 0.0082 MMY10014 D-Pd All treated (89% len-refractory) n = 103 Median: 9.9 mo 24-mo PFS rate: 31% 66% 7% ENDEAVOR5,6 Kd vs Vd Len-refractory Kd: n = 113 Vd: n = 122 Median: 8.6 mo vs 6.6 mo5 HR: 0.80; 95% CI, 0.57-1.116 N/R N/R MM-0037 P-low d vs high d Len-refractory P-low d: n = 286 High d: n = 141 Median: 3.9 mo vs 1.9 mo HR: 0.50; 95% CI, 0.40-0.62 30% vs 9% P <0.0001 N/R Addition of DARA to SOC is effective in len-refractory RRMM 1. Harousseau JL and Attal M. Blood 2017;130:963-973. 2. Sengsayadeth S, et al. Blood Cancer J 2017;7(3):e545. 3. Lentzsch S, et al. Oral presentation at JSH, Oct 20-22, 2017; Tokyo, Japan; Abstract OS3-12D2. 4. Facon T, et al. Poster presented at ASH, Dec 9-12, 2017; Atlanta, GA; Abstract 1824. 5. Moreau P, et al. Leukemia 2017;31:115-122. 6. Dimopoulos MA, et al. Lancet Oncol 2016;17(1):27-38. 7. San-Miguel J, et al. Lancet Oncol 2013;14(11):1055-1066. Ajai Chari, MD Len, lenalidomide; Vd, bortezomib/dexamethasone; PFS, progression-free survival; ORR, overall response rate; MRD, minimal residual disease; HR, hazard ratio; Pd, pomalidomide/dexamethasone; Kd, carfilzomib/dexamethasone; N/R, not reported; SOC, standard of care. 1 4 Study Design: D-Kd Arm of MMY1001 • • Open-label, nonrandomized, multicenter, phase 1b study in RRMM patients Per protocol, DARA was administered as a single first dose (n = 10) or as a split first dose (n = 75) Eligibility/treatment • Relapsed MM – 1-3 prior lines of therapy, including bortezomib and an IMiD – Len-refractory pts allowed • Carfilzomib-naïve • ECOG status ≤2 Dosing schedule (28-day cycles) Split first dosea: 8 mg/kg Days 1-2 of Cycle 1 Single first dose: 16 mg/kg on C1D1 16 mg/kg IV QW on Cycles 1-2, Q2W on Cycles 3-6, and Q4W thereafter until PD Carfilzomibb: • LVEF ≥40% • • ANC ≥1 × 109/L • • Platelet count ≥75 × 109/L • Safety, tolerability • • • 20 mg/m2 Endpoints Primary DARA: IV Cycle 1 Day 1 Secondary • ORR and duration of response • OS Exploratory • PFS • MRD (NGS)c Escalated to 70 mg/m2 Cycle 1 Day 8+; weekly (Days 1, 8, 15) until PD Dexamethasone: 40 mg/week (Days 1, 8, 15, 22) IV or PO until PD • PK aIn 500-mL dilution volume. 20 mg/m2 and 70 mg/m2 were administered as 30-min IV infusions. patients evaluated for MRD, MRD was assessed using NGS at time of suspected CR and at 12 and 18 mo after initial dose. In cases where daratumumab is suspected of interfering with IFE and preventing clinical CR response calls, subjects with VGPR may also be evaluated for MRD. bBoth c Among Ajai Chari, MD ECOG, Eastern Cooperative Oncology Group; LVEF, left ventricular ejection fraction; ANC, absolute neutrophil count; QW, every week; Q2W, every 2 weeks; Q4W, every 4 weeks; IV, intravenous; PO, oral; OS, overall survival; MRD, minimal residual disease; NGS, next generation sequencing; PK, pharmacokinetic; IFE, immunofixation; IRR, infusion-related reaction. 1 5 5 6/18/2018 Infusion Rates and IRRs: Split First Dose DARA (All Treated) Split first dose IRRs (>1 patient) during all infusions Single first infusion (n = 10) Cycle 1 Day 1 Split first infusion (n = 75) Cycle 1 Day 1 Cycle 1 Day 2 Total 43 IRR, n (%) Median (range) infusion time Allergic rhinitis 5 (50.0%) 7.1 (6.5-8.9) h Throat irritation 4 Dyspnea 4 27 (36.0%) 3 (4.0%) 4.3 (3.9-10.6) h 4.2 (3.9-8.6) h Nausea 4 8 Vomiting 8 Pyrexia 4 Flushing • IRR % and infusion times were consistent between single and split first dose for subsequent infusions 4 Cough 3 Nasal congestion 3 Chills 3 Hypertension 3 0 10 20 30 40 50 IRRs, % Split first dose of DARA is feasible and improves patient convenience IRR, infusion-related reaction. Ajai Chari, MD PFS • Median follow up: 12.0 months 12-month PFS 100 % surviving without progression 90% 80 Len-exposed 71% 60 All-treated 62% Len-refractory Median: 14.1 mo (95% CI, 12.0-NE) 40 20 0 No. at risk All-treated Len-refractory Len-exposed 0 3 6 9 85 51 30 72 41 27 66 35 27 60 32 25 12 15 18 21 24 13 6 7 11 5 6 8 3 5 0 0 0 Months 26 12 13 PFS benefit observed in len-refractory patients Ajai Chari, MD What about Pomalidomide ? 6 6/18/2018 Efficacy Results of Pomalidomide + LoDEX in advanced RR MM (Phase II/III Studies MM002 & MM003) Percentage response 50 40 12 MR PR VGPR CR/sCR 8 30 20 30 24 ORR = 33% ORR = 32% 10 7 1 MM-003 3 MM-002 0 MM-0021 MM-0032,3 Median follow-up, months 14.2 15.4 Median DoR, months 8.3 Median PFS, months 4.2 4.0 Median OS, months 16.5 13.1 7.5 1.Richardson PG, et al. Blood 2014;123:1826-32. 2. San Miguel J, et al. Lancet Oncology 2013;14:1055-1066. 3. San Miguel et al: ASH 2013; Oral Presentation and Abstract 686. CR, complete response; DoR, duration of response; LoDEX, low-dose dexamethasone; MR, minimal response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; POM, pomalidomide; PR, partial response; sCR, stringent complete response; VGPR, very good partial response. Efficacy Results of POM-based Triple Therapy Combinations in Advanced RRMM 100 MR PR VGPR CR 90 Percentage response 80 13 38 70 60 7 20 20 ORR 94% 50 40 30 ORR 61% ORR 51% 20 10 0 Study 25 41 27 32 ORR 70% ORR 48% 37 31 18 15 5 5 POM+PRED+Cy POM+DEX+Cla 15 1 POM+DEX±Cy Larocca1 26 43 7 0 POM+DEX+BORT POM+DEX+CFZ POM+DEX+BORT (MM-005) Mark2 Baz3 Mikhael4 Shah5 Phase 1/2 2 1/2 2 1/2 N 55a 114 70 16 79 Population a Data 1–3 prior therapies; LEN-relapsed or refractory ≥ 3 prior therapies including LEN (not all refractory) ≥ 2 prior therapies; LEN-refractory ORR 70% 27 1–4 prior therapies, resistant or refractory to LEN Relapsed and/or refractory; LEN-refractory Richardson6 1/2 27 1-4 prior therapies; LEN-refractory, prior BORT 1. Larocca A, et al. Blood. 2013;122:2799−2806. 2. Mark et al: ASH 2013; Poster Presentation and Abstract 1955.. 3. Baz et al: ASH 2013; Poster Presentation and Abstract 3200. Mikhael J et al. ASH 2013; Poster Presentation and Abstract 1940. 5. Shah et al: ASH 2013; Oral Presentation and Abstract 690. 6. Richardson et al: ASH 2013; Oral Presentation and Abstract 8589. reported here for MTD and Phase II pts only BORT, bortezomib; CFZ, carfilzomib; Cla, clarithromycin; CR, complete response; Cy, cyclophosphamide; DEX, dexamethasone ; LEN, lenalidomide; LoDEX, low-dose dexamethasone ; MR, minimal response; ORR, overall response rate; POM, pomalidomide; PR, partial response; PRED, prednisone; VGPR, very good partial response. 4. OPTIMISMM Study Design and methods 4 mg days 1-14/21 1.3 mg/m2 cycles 1-8: days 1, 4, 8, 11/21 cycles 9+: days 1 and 8/21 20 mg (≤ 75 y) or 10 mg (> 75 y) day of and day after BORT LoDEX Vd (n = 278) BORT (N = 559) LoDEX • Stratification • 1.3 mg/m2 cycles 1-8: days 1, 4, 8, 11/21 cycle 9+: days 1 and 8/21 20 mg (≤ 75 y) or 10 mg (> 75 y) day of and day after BORT PD or Unacceptable Toxicity • 1-3 prior regimens including ≥ 2 cycles of LEN Tx • ECOG PS ≤ 2 • Prior BORT Tx allowed (except if PD with twice weekly dose)a POM BORT PD, subsequent antimyeloma Tx, and survival LT follow-up PVd (n = 281) RRMM Study endpoints – age (≤ 75 y vs > 75 y) – Primary: PFS – number of prior antimyeloma regimens (1 vs > 1) – Secondary: OS, ORR by IMWG criteria, DOR, safety – β2-microglobulin levels at screening (< 3.5 mg/L vs ≥ 3.5 to ≤ 5.5 mg/L vs > 5.5 mg/L) – Key exploratory: TTR, PFS2, efficacy analysis in subgroups a Patients • Data cutoff: October 26, 2017 with PD during therapy or within 60 days of the last dose of a BORT-containing therapy under the approved dosing schedule of 1.3 mg/m2 twice weekly were excluded. BORT, bortezomib; DOR, duration of response; IMWG, International Myeloma Working Group; LT, long-term; PFS2, progression-free survival after next line of therapy; TTR, time to response. 21 7 6/18/2018 Progression-Free Survival (ITT Population) • OPTIMISMM met its primary endpoint, demonstrating a clinically meaningful and statistically significant improvement in PFS with PVd vs Vd Events/N Median PFS, mo HR (95% CI) P Value 0.9 PVd 154/281 11.20 0.8 Vd 162/278 7.10 0.61 (0.49-0.77) < .0001 Probability of Progression-Free Survival 1.0 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 No. at Risk PVd Vd 0 3 6 9 12 15 18 281 278 233 176 182 112 128 66 94 42 67 30 47 20 21 24 Months 28 14 13 4 27 30 33 36 39 42 45 7 4 4 3 2 2 1 2 1 0 1 0 0 0 Abstract 8001 : OPTIMISMM—Paul Richardson, MD What is New in MM Oral proteasome inhibitors HDACi Kinase inhibitors Monoclonal antibodies Novel mechanism s Immunotherapies • Panobinost at • Vermurafeni b • Elotuzumab • Venetoclax • PDL-1/PD-1 • Ricolinostat • Afuresertib • Daratumuma b • Selinexor • CAR-T • ACY 241 • Dinaciclib • Isatuximab New IMiDs • Ixazomib • CC-122 • Oprozomib • CC-220 • Marizomib • BITE • PIM (LGH447) • Trametinib HDACi, histone deacetylase inhibitor Oprozomib in Myeloma: still in development Authors’ Conclusions The most common grade ≥3 nonhematologic AEs were diarrhea, nausea, and vomiting; rates of treatment-emergent PN and rash were low. Recommended phase 2 dose and schedule: 240/300 mg/day in the 2/7 step-up schedule and 150/180 mg/day in the 5/14 step-up schedule. Preliminary data suggest that step-up dosing is associated with improved tolerability. Enrollment of patients with MM continues both schedules in the phase 2 study with a target of 94 patients; all patients are now receiving a new (extendedrelease) formulation of oprozomib. Single-agent oprozomib has promising antitumor activity, with responses observed in patients who had carfilzomib-refractory MM. Vij R et al. Blood. 2014;124. Abstract 34. 8 6/18/2018 CC-122: New IMiD Ribrag V, et al. Blood. 2014;124 [poster 3500]. 25 Venetoclax Background ▪ BCL-2 and MCL-1 promote multiple myeloma (MM) cell survival ▪ Venetoclax is a selective, orally available small molecule BCL-2 inhibitor1 and bortezomib can indirectly inhibit MCL-1 ▪ Venetoclax enhanced bortezomib activity in vitro and in vivo2 1. Roberts AW et al. NEJM 2015 2. Punnoose E et al. Mol Cancer Ther 2016 Phase 1 Venetoclax for RRMM: response and TTP in all patients and by t(11;14) status sC R CR VGPR PR 10% 30 O R R 21% 3% D u r a tio n o f O v e r a ll R e s p o n s e A ll P a tie n ts A ll P a tie n ts 100 t(1 1 ;1 4 ) 4% 20 T im e to P r o g r e s s io n 100 O R R 40% 40 % N o t P ro g re s s e d P e rc e n ta g e o f P a t ie n t s 50 13% t(1 1 ;1 4 ) n o n -t(1 1 ;1 4 ) 75 50 n o n -t(1 1 ;1 4 ) 75 50 25 25 4% 0 10 0 0 8% 13% 3% 6% 3% 0 2 4 O R R 6% A ll P a t ie n t s t( 1 1 ; 1 4 ) n o n -t(1 1 ;1 4 ) N=66 n=30 n=36 6 8 10 12 14 16 18 20 22 24 0 2 M o n th s s in c e firs t d o s e 4 6 8 10 12 14 16 18 20 22 24 M o n th s s in c e fir s t re s p o n s e N o . a t ris k 6 6 3 3 2 7 2 0 1 6 9 3 1 1 1 1 1 14 14 13 13 9 3 2 1 1 1 1 N o . a t ris k 3 0 2 0 1 9 1 7 1 3 7 2 1 1 1 1 1 12 12 11 11 8 3 2 1 1 1 1 N o . a t ris k 3 6 1 3 2 1 8 3 3 2 2 2 2 1 Data cutoff of 19Aug2016 Kumar ASH 2016 Abstract 488 9 6/18/2018 Ph 1: Venetoclax in combination with Btz+Dex Ven (50-500mg po daily); Btz (1.3mg/msq days 1,4,8,11); Dex (20mg days 1-2, 4-5, 8-9, 11-12) x8 cycles N=32 Criteria Response % (36 pts) Cytogenetics ORR % (36 pts) CR 9% (3) t(11;14) (n=4) 75% VGPR 11% (4) t(4;14) (n=3) 33% PR 25% (10) del17p (n=8) 25% Hyperdiploid (n=14) 64% DOR median 6mos. A Phase 3, multicenter, randomized, double blind, placebo-controlled study of venetoclax plus bortezomib and dexamethasone in subjects with relapsed or refractory myeloma in 1-3 prior lines of therapy and are sensitive or naïve to proteasome inhibitors Chanan-Khan Lugano 2015 Selinexor Mechanism of Action ▪ Exportin 1 (XPO1) is the only nuclear exporter for the majority of tumor suppressor proteins (TSPs), the glucocorticoid receptor (GR), and eIF4Ebound oncoprotein mRNAs ▪ Selinexor is a first-in-class XPO1 inhibitor that induces nuclear retention and activation of TSPs and the GR in the presence of steroids and suppresses oncoprotein expression 29 Tracking Genetic Hetrogeneity BRAF c.1799T>A, p.V600E Genomic control Myeloma-GT BM and Blood Biopsies Lohr et al, Science Trans Med 2016 10 6/18/2018 BASKET STUDY: VEMURAFENIB for BRAF mutant MM (n=9) Raje et al, ASH 2015 An open-label, pilot study of dabrafenib and/or trametinib in patients with relapsed and/or refractory multiple myeloma Jens Lohr, MD PhD Noopur Raje, MD 11 6/18/2018 GSK 2857916:Background ▪ ▪ ▪ BCMA: expressed on differentiated B cells; requisite for long-lived plasma cells’ survival BCMA is broadly expressed on malignant plasma cells GSK2857916: humanized, afucosylated IgG1 anti-BCMA antibody; neutralization of soluble BCMA ▪ Four mechanisms of action: 1. ADC mechanism 2. ADCC mechanism 3. Immunogenic cell death 4. BCMA receptor signaling inhibition ADC Preclinical studies demonstrate its selective and potent activity1 1 1 BCMA BCMA GSK2857916 3 3 4 – MMAF (non-cell permeable, highly potent auristatin ADCC Effector cell 2 Malignant plasma cell Afucosylation – Enhanced ADCC Linker BCMA BCMA 4 Fc receptor x Cytotoxic agent Lysosome – Stable in circulation Cell death 1Tai YT, et al. Blood 2014;123(20):3128-38. ADC, antibody-drug conjugate; ADCC, antibody-dependent cell-mediated cytotoxicity; BCMA, B-cell maturation antigen; IgG, immunoglobulin G; MMAF, monomethyl auristatin-F DREAMM-1 Part 2: Maximum % Reduction in M-Protein or Free Light Chain from Baseline ORR = 21/35 (60%; 95% CI: 42.1%, 76.1%) • 1 sCR, 2 CR, 15 VGPR, 3 PR * *One patient with a VGPR had a <90% reduction in serum M-protein due to missing laboratory data, which was confirmed by investigators as too small to quantify after the data cut-off CI, confidence interval; CR, complete response; FLC, free light chain; M-protein, myeloma protein; ORR, overall response rate; PD, progressive disease; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response DREAMM-1 Part 2: Efficacy – Progression-free Survival and duration of response Number of subjects Progressed or died Censored, f/u ended Censored, f/u ongoing 35 15 (43%) 3 (9%) 17 (49%) Number of subjects Progressed or died Censored, f/u ended Censored, f/u ongoing 21 4 (19%) 0 17 (81%) Progression-free survival (months) Q1 (95% CI) Median (95% CI) Q3 (95% CI) 2.3 (0.7, 6.8) 7.9 (3.1, -) N/A Duration of response (months) Q1 (95% CI) Median (95% CI) Q3 (95% CI) 6.7 (1.6, -) N/A (6.7, -) N/A CI, confidence interval; f/u, follow-up; N/A, not available; Q, quartile 3 6 12 6/18/2018 Chimeric Antigen Receptor (CAR) T cells bb2121: AN OPTIMAL BCMA CAR T CELL DESIGN bb2121 CAR Design MND SP Anti-BCMA scFv Promoter CD8 4-1BB CD3z Linker Signaling Domains Tumor binding domain • Autologous T cells transduced with a lentiviral vector encoding a CAR specific for human BCMA • State of the art lentiviral vector system • Optimal 4-1BB costimulatory signaling domain: associated with less acute toxicity and more durable CAR T cell persistence than CD28 costimulatory domain1 1. Ali SI, et al. Blood. 2016;128(13):1688-700. PROGRESSION-FREE SURVIVAL • mPFS of 11.8 months at active doses (≥150 × 106 CAR+ T cells) in 18 subjects in dose escalation phase • mPFS of 17.7 months in 16 responding subjects who are MRD-negative PFS at Inactive (50 × 106) and Active (150–800 × 106) Dose Levelsa mPFS = 11.8 mo PFS in MRD-Negative Patientsa mPFS = 17.7 mo mPFS = 2.7 mo Data cutoff: March 29, 2018. Median and 95% CI from Kaplan-Meier estimate. NE, not estimable. a PFS in dose escalation cohort. 13 6/18/2018 Current Understanding • Combinations will allow us to improve responses and cure a higher fraction of patients. • Drugs with different MOA will overcome genetic heterogeneity • High risk disease can be identified and specifically targeted 14 6/18/2018 Future Directions in Myeloma Post ASCO: Clinical Trials Krina Patel MD MSc Assistant Professor Department of Lymphoma/Myeloma University of Texas MD Anderson Cancer Center Optimizing Dosing Schedule Once-weekly Versus Twice-weekly Carfilzomib Dosing in Patients with Relapsed and Refractory Multiple Myeloma: Results of the Randomized Phase 3 Study A.R.R.O.W. Presented By Maria-Victoria Mateos at 2018 ASCO Annual Meeting 1 6/18/2018 A.R.R.O.W. Study Rationale Presented By Maria-Victoria Mateos at 2018 ASCO Annual Meeting A.R.R.O.W. Study Design Presented By Maria-Victoria Mateos at 2018 ASCO Annual Meeting Primary Endpoint: PFS
Presented By Maria-Victoria Mateos at 2018 ASCO Annual Meeting 2 6/18/2018 Overall Response Rates Presented By Maria-Victoria Mateos at 2018 ASCO Annual Meeting Adverse Events Summary
Presented By Maria-Victoria Mateos at 2018 ASCO Annual Meeting Adverse Events of Interest Presented By Maria-Victoria Mateos at 2018 ASCO Annual Meeting 3 6/18/2018 Overall Survival (OS) Presented By Maria-Victoria Mateos at 2018 ASCO Annual Meeting Conclusions Presented By Maria-Victoria Mateos at 2018 ASCO Annual Meeting Maintenance Revlimid Does dose matter? 4 6/18/2018 Maintenance Therapy with 25 versus 5 mg Lenalidomide after Prolonged Lenalidomide Consolidation Therapy
in Newly-Diagnosed, Transplant-Eligible Patients with Multiple Myeloma Presented By Elizabeth O''Donnell at 2018 ASCO Annual Meeting Study Design Presented By Elizabeth O''Donnell at 2018 ASCO Annual Meeting Dosage Presented By Elizabeth O''Donnell at 2018 ASCO Annual Meeting 5 6/18/2018 Response Presented By Elizabeth O''Donnell at 2018 ASCO Annual Meeting EFS and OS Presented By Elizabeth O''Donnell at 2018 ASCO Annual Meeting Safety Presented By Elizabeth O''Donnell at 2018 ASCO Annual Meeting 6 6/18/2018 Conclusions Presented By Elizabeth O''Donnell at 2018 ASCO Annual Meeting Targeted therapy Phase 2 Study of Venetoclax Plus Carfilzomib and Dexamethasone in Patients With Relapsed/Refractory Multiple Myeloma Presented By Luciano Costa at 2018 ASCO Annual Meeting 7 6/18/2018 Study Overview Presented By Luciano Costa at 2018 ASCO Annual Meeting Dosing Presented By Luciano Costa at 2018 ASCO Annual Meeting Enrollment and Patient Disposition Presented By Luciano Costa at 2018 ASCO Annual Meeting 8 6/18/2018 Summary of Safety (N=42) Presented By Luciano Costa at 2018 ASCO Annual Meeting Objective Responses in All Patients and Those Refractory to PIs and IMiDs Presented By Luciano Costa at 2018 ASCO Annual Meeting Conclusions Presented By Luciano Costa at 2018 ASCO Annual Meeting 9 6/18/2018 New combinations with “old”drugs abstract 8001 Presented By Paul Richardson at 2018 ASCO Annual Meeting Phase 3 OPTIMISMM Study Design Presented By Paul Richardson at 2018 ASCO Annual Meeting 10 6/18/2018 Patient Disposition (ITT) Presented By Paul Richardson at 2018 ASCO Annual Meeting Progression-Free Survival (ITT) Presented By Paul Richardson at 2018 ASCO Annual Meeting Response Presented By Paul Richardson at 2018 ASCO Annual Meeting 11 6/18/2018 Conclusions and future directions Presented By Paul Richardson at 2018 ASCO Annual Meeting Improving Monoclonal Antibodies A phase II study of elotuzumab in combination with pomalidomide, bortezomib and dexamethasone (Elo–PVD) in relapsed and refractory myeloma (abstract 8012)
Presented By Rachid Baz at 2018 ASCO Annual Meeting 12 6/18/2018 Elo-PVD Results Presented By Rachid Baz at 2018 ASCO Annual Meeting Subcutaneous daratumumab in patients with relapsed or refractory multiple myeloma (RRMM): Part 2 update of the open label, multicenter, dose escalation Phase Ib study (PAVO) (abstract 8013) Presented By Rachid Baz at 2018 ASCO Annual Meeting Dara IV or SC? Presented By Rachid Baz at 2018 ASCO Annual Meeting 13 6/18/2018 Phase 1b Study of Isatuximab and Carfilzomib for the Treatment of Relapsed and/or Refractory Multiple Myeloma (abstract 8014) Presented By Rachid Baz at 2018 ASCO Annual Meeting KD with Isa or Dara? Presented By Rachid Baz at 2018 ASCO Annual Meeting Conclusions • Available myeloma treatments are increasing at a rate higher than ever before. • Trials are aimed at continuing to improve efficacy as well as quality of life. • Optimal combinations of the varying categories of treatments and sequence of these combinations needs continued evaluation. 14 6/18/2018 Thank you! Slides from ASCO meeting library kpatel1@mdanderson.org 15 6/18/2018 Future Role of CAR T Therapies in Multiple Myeloma Nina Shah University of California San Francisco B cell maturation antigen (BCMA) • Consistently expressed on plasma cells/MM cells1 • Possibly protects MM cells in BM niche2 • BMCA expression increases with disease progression3 • Limited expression on normal, non-hematopoietic cells1 1. Carpenter et al, Clinical Cancer Research, 2013 2. Novak et al, Blood 2004 3. Sanchez, 2012 1 6/18/2018 Summary of ongoing BCMA CAR-T Trials for MM Name Anti-BCMA CAR Bb2121 LCAR-B38M CART-BCMA Group NCI Bluebird/Celgene Nanjng/Legend Biotech Novartis/Penn Murine/CD3ζ, 41BB Murine/CD3ζ, 41BB Fully human/CD3ζ, 41BB Binder/costimulatory Murine/CD3ζ, CD28 signal Transfection γ-retroviral Lentiviral Lentiviral Lentiviral BCMA expression required? Yes Yes Yes No ABSTRACT 8007 bb2121 Anti-BCMA CAR T Cell Therapy in Patients With Relapsed/Refractory Multiple Myeloma: Updated Results From a Multicenter Phase I Study Noopur Raje, MD,1 Jesus Berdeja, MD,2 Yi Lin, MD, PhD,3 Nikhil Munshi, MD,4 David Siegel, MD, PhD,5 Michaela Liedtke, MD,6 Sundar Jagannath, MD,7 Deepu Madduri, MD,7 Jacalyn Rosenblatt, MD,8 Marcela Maus, MD, PhD,1 Ashley Turka,9 Lyh Ping Lam, PharmD,9 Richard A. Morgan, PhD,9 M. Travis Quigley,9 Monica Massaro, MPH,9 Kristen Hege, MD,10 Fabio Petrocca, MD,9 and James N. Kochenderfer, MD11 1Massachusetts General Hospital Cancer Center, Boston, MA; 2Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN; 3Mayo Clinic, Rochester, MN; Institute, Boston, MA; 5Hackensack University Medical Center, Hackensack, NJ; 6Stanford University Medical Center, Palo Alto, CA; 7Mount Sinai Medical Center, New York, NY; 8Beth Israel Deaconess Medical Center, Boston, MA; 9bluebird bio, Inc, Cambridge, MA; 10Celgene Corporation, San Francisco, CA; 11Experimental Transplantation and Immunology Branch, National Cancer Institute/National Institutes of Health, Bethesda, MD 4Dana-Farber Cancer CRB-401 PHASE 1 STUDY DESIGN Flu 30 m/m 2 Cy 300 mg/m2 Dose Escalation (N=21) Dose Expansion (N=22) ≥50% BCMA expression <50% BCMA expression (n=10) 50 × 106 150 × 106 450 × 106 800 × 106 ≥50% BCMA expression (n=12) Dose range: 150–450 × 106 CAR+ cells Manufacturing success rate of 100% 2 6/18/2018 TREATMENT HISTORY Escalation (N=21) 7 (3, 14) 21 (100) 0 15 (71) 6 (29) Escalation (N=21) Median (min, max) prior regimens Prior autologous SCT, n (%) 0 1 >1 Expansion (N=22) 8 (3, 23) 19 (86) 3 (14) 14 (64) 5 (23) Expansion (N=22) Exposed Refractory Exposed Refractory 21 (100) 14 (67) 22 (100) 16 (73) Carfilzomib 19 (91) 12 (57) 21 (96) 14 (64) Lenalidomide 21 (100) 19 (91) 22 (100) 18 (82) Pomalidomide 19 (91) 15 (71) 22 (100) 21 (96) Prior therapies, n (%) Bortezomib Daratumumab Exposed/Refractory, n (%) Bort/Len 15 (71) 10 (48) 22 (100) 19 (86) 21 (100) 14 (67) 22 (100) 14 (64) Bort/Len/Car/Pom/Dara 15 (71) 6 (29) 21 (96) 7 (32) Data cutoff: March 29, 2018. SCT, stem cell transplant. ADVERSE EVENTS OF SPECIAL INTEREST TEAE, n (%) Overall Grade ≥3 Cytokine release syndromea 27 (63) 2 (5) Neurotoxicityb 14 (33) 1 (2) Neutropenia 35 (81) 34 (79) Thrombocytopenia 26 (61) 22 (51) Anemia 24 (56) 19 (44) Infectionc Overall First Month 26 (61) 10 (23) 9 (21) 2 (5) • No grade 4 CRS events • No fatal CRS or neurotoxicity events Time to Recovery of Grade 3/4 Cytopenias in Patients Without Recovery by Month 1d Probability of Recovery, % CAR T Treatment-Emergent Adverse Events All Infused Patients (N=43) Events Median (95% CI), mo Neutropenia (n=9) 7 2 (1.2–2.6) Thrombocytopenia (n=18) 10 3 (1.9–NE) Time After bb2121 Infusion, monthse • 31/40 (78%) recovered ANC to ≥1000/µL by Day 32 • 22/40 (55%) recovered PLT to ≥50,000/µL by Day 32 Data cutoff: March 29, 2018. NE, not estimable. aCRS uniformly graded per Lee DW, et al. Blood. 2014;124(2):188-195. bEvents occurring in first 28 d and including dizziness, bradyphrenia, somnolence, confusional state, nystagnmus, insomnia, memory impairment, depressed level of consciousness, neurotoxicity, lethargy, tremor and hallucination. cIncludes the SOC Infections and Infestations. Events observed in >10% include upper respiratory tract infection and pneumonia. dIncludes patients treated with active doses (150–800 × 106 CAR+ T cells; N=40). Median and 95% CI from Kaplan-Meier estimate. eTime from first bb2121 infusion to the first grade ≤2 event after day 32. CYTOKINE RELEASE SYNDROME: MOSTLY LOW GRADE AND MANAGEABLE Cytokine Release Syndrome By Dose Level Cytokine Release Syndrome Parameters Patients with a CRS event, n (%) Dosed Patients (N=43) 100 27 (63) 80 Maximum CRS gradea None 1 2 3 4 16 (37) 16 (37) 9 (21) 2 (5) 0 Median (min, max) time to onset, d 2 (1, 25) Median (min, max) duration, d 6 (1, 32) Tocilizumab use, n (%) 9 (21) Corticosteroid use, n (%) 4 (9) 90 Patients, % Parameter Maximum Toxicity Gradea 3 2 1 82% 9.1 70 22.7 60 50 40 30 39% 22.2 50.0 20 10 0 16.7 150x×106 106 150 (n=18) >150 x× 106 106 >150 (n=22) Dose Levelb Data cutoff: March 29, 2018. a CRS uniformly graded according to Lee DW, et al. Blood. 2014;124(2):188-195. b3 patients were treated at the 50 x 106 dose level for a total of 43 patients. 3 6/18/2018 TUMOR RESPONSE: DOSE-RELATED; INDEPENDENT OF TUMOR BCMA EXPRESSION Tumor Response By Dosea Objective Response Rate, % 90 80 60 40 ORR=33.3% mDOR=1.9 mo 10 36.4 33.3 7.1 7.1 9.1 50 ×x 106 106 (n=3) 150 x× 106 106 (n=14) >150 x× 106 106 (n=22) 84 (59, 94) 87 (36, 638) 194 (46, 556) 0 Median follow-up (min, max), d 50.0 42.9 30 20 ORR=100% 100 ORR=91% 90 ORR=57.1% mDOR=NE 70 50 Tumor Response By BCMA Expressiona ORR=95.5% mDOR=10.8 mo sCR/CR VGPR PR Objective Response Rate, % 100 37.5 80 sCR/CR VGPR PR 70 54.5 60 50 40 50.0 30 27.3 20 10 0 Median follow-up (min, max), d 12.5 9.1 6 450x ×106 10low 450 Low BCMA (n=8) 6 450x 106 × 10high 450 High BCMA (n=11) 311 (46, 556) 168 (121, 184) Data cutoff: March 29, 2018. CR, complete response; mDOR, median duration of response; ORR, objective response rate; PD, progressive disease; PR, partial response; sCR, stringent CR; VGPR, very good partial response. aPatients with ≥2 months of response data or PD/death within <2 months. ORR is defined as attaining sCR, CR, VGPR, or PR, including confirmed and unconfirmed responses. Low BCMA is <50% bone marrow plasma cells expression of BCMA; high BCMA is defined as ≥50%. PROGRESSION-FREE SURVIVAL • mPFS of 11.8 months at active doses (≥150 × 106 CAR+ T cells) in 18 subjects in dose escalation phase • mPFS of 17.7 months in 16 responding subjects who are MRD-negative PFS at Inactive (50 × 106) and Active (150–800 × 106) Dose Levelsa Events mPFS (95% CI), mo 50 × 106 (n=3) 150–800 × 106 (n=18) 3 2.7 (1.0–2.9) 10 11.8 (8.8–NE) PFS in MRD-Negative Patients 150–800 × 106 (n=16) mPFS (95% CI), mo mPFS = 11.8 mo 17.7 (5.8–NE) mPFS = 17.7 mo mPFS = 2.7 mo Data cutoff: March 29, 2018. Median and 95% CI from Kaplan-Meier estimate. NE, not estimable. aPFS in dose escalation cohort. Summary of ongoing BCMA CAR-T Trials for MM Name Anti-BCMA CAR Bb2121 Group NCI Bluebird/Celgene Murine/CD3ζ, CD28 Murine/CD3ζ, 4-1BB Murine/CD3ζ, 41BB Fully human/CD3ζ, 4-1BB γ-retroviral Lentiviral Lentiviral Lentiviral Yes Yes Yes No 7, 11 7 3 9 Efficacy 1 sCR (relapsed), 1 VGPR, 2 PR, 8 SD Responses in highest cell dose; 9/11 in top dose 33 CR or VGPR, n=35, 1 relapse; 5 MRD neg > 1 yr 6/9, 2/5, 5/6 responses in 3 cohorts Safety Toxicity substantial (Gr3-4CRS) but reversible esp in highest doses (9 e6/kg); protocol modified to pts with lower tumor burden 10 CRs, 6 VGPR, 1 PRs (4 eventual PD), n=18 at >5 e7 : 94% RR 9 MRD neg CRS in 71%; transient Gr3 10%; 5 deaths (cardio-pulm arrest, unrelated, 1 MDS, 3 PD at lowest dose) Early report of 1 Gr 4 neurotoxicity Transient CRS 29/35, no neurotox CRS in 17/21 pts (6 with Gr2), with neurotox in 3 pts 1 death – candidemia/PD Binder/costimulatory signal Transfection BCMA expression required? Median prior lines of tx LCAR-B38M Nanjng/Legend Biotech CART-BCMA Novartis/Penn 4 6/18/2018 JNJ-68284528 (LCAR-B38M CAR-T cells) Genetically modified autologous T-cell immunotherapy directed at B-cell maturation antigen (BCMA) which is being developed for the treatment of Multiple Myeloma VHH 2 different anti-BCMA VHH domains for enhanced avidity –T cell function is avidity driven VHH 4-1BB: built-in “2nd Signal” costimulatory signaling CD3z: TCR-like activation Linker = (Glycine)4Serine JNJ-528 is a unique bispecific CAR that binds with high affinity to 2 different epitopes on BCMA, enabling tight binding of the CAR to the BCMA-expressing cells Courtesy of Janssen 16 JNJ-68284528 (LCAR-B38M) CAR T cell: designed for high affinity interaction with BCMA-expressing tumor cells Conventional CAR-T LCAR-B38M VHH multi-specific CAR Target A BCMA scFv-Conventional CAR Target B VHH-Bi-epitope CAR VHH-multi-specific CAR Courtesy of Janssen Summary of ongoing BCMA CAR-T Trials for MM Name Anti-BCMA CAR Bb2121 Group NCI Bluebird/Celgene Murine/CD3ζ, CD28 Murine/CD3ζ, 4-1BB Murine/CD3ζ, 41BB Fully human/CD3ζ, 4-1BB γ-retroviral Lentiviral Lentiviral Lentiviral Yes Yes Yes No 7, 11 7 3 9 Efficacy 1 sCR (relapsed), 1 VGPR, 2 PR, 8 SD Responses in highest cell dose; 9/11 in top dose ORR= 57% , 96% in pts @>150 e6; mPFS 11.8 mo, 17.7 mo in MRD neg pts 33 CR or VGPR, n=35, 1 relapse; 5 MRD neg > 1 yr 6/9, 2/5, 5/6 responses in 3 cohorts Safety Toxicity substantial (Gr3-4CRS) but reversible esp in highest doses (9 e6/kg); protocol modified to pts with lower tumor burden CRS in 71%; transient Gr3 10%; 5 deaths (cardio-pulm arrest, unrelated, 1 MDS, 3 PD at lowest dose) Early report of 1 Gr 4 neurotoxicity Transient CRS 29/35, no neurotox CRS in 17/21 pts (6 with Gr2), with neurotox in 3 pts 1 death – candidemia/PD Binder/costimulatory signal Transfection BCMA expression required? Median prior lines of tx LCAR-B38M Nanjng/Legend Biotech CART-BCMA Novartis/Penn 5 6/18/2018 Challenges in CAR T therapy for MM • CRS (hopefully not as much of an issue as with ALL) • Persistence • Lymphodepletion • Cytokine-based T-reg elimination • Virus-specific T cells as primary CAR-T population Virus-specific T cells as primary CAR-T population 1. Maus et al, CCR 2016 Challenges in CAR T therapy for MM • CRS (hopefully not as much of an issue as with ALL) • Persistence • Lymphodepletion • Cytokine-based T-reg elimination • Virus-specific T cells as primary CAR-T population • Optimizing co-stimulatory signaling • 41BB>CD28 • Nature of MM is waxing and waning, should the cells be that way as well? • “ON-switch” CARs • Targeting multiple antigens • T cells redirected for universal cytokine-mediated killing (TRUCKs) 6 6/18/2018 “On” switch CAR T cells 1. Roybal et al, Cell 2016 T cells redirected for universal cytokinemediated killing (TRUCKs) 1. Chiemelewski et al, Immunological Reviews, 2013 Cellectis Universal SLAMF7-Specific CAR T (abs 502) • “Off-the-shelf” • Normal healthy PB donors • Inactivation of the TCRα constant (TRAC) gene using TALEN® gene-editing technology to prevent GVHD and expression of T cell SLAMF7. 7 6/18/2018 Poseida: CARTyrin (abs 3068) • DNA transposon system • iCasp9-based safety switch • Anti-BCMA CARTyrin • Selection gene (~ 100% pure CAR+ product) • Enrich stem cell memory T cell subset But where are we really going…? • Timing of CART • Disease burden • Position relative to autologous transplant • Cost • Time and financial cost of proving superiority • Clinical trial design • MRD as endpoint “It’s my CAR-T and I’ll cry if I want to…” • Persistence • Inducibility 8 6/18/2018 Case • 65 YO M without significant PMH presents with new back pain and incidentally found abnormal protein level • Further work-up shows IgG kappa M-spike 3.8 g/dL • Additional labs: normal Cr, Ca; Hb=11.8 g/dL • MRI shows new L4 compression fracture • BM biopsy: 60% kappa-restricted plasma cells, normal cytogenetics, FISH positive for t(11;14) Treatment course • VRD induction→ achieves VGPR after 6 cycles • Mel 200 ASCT→ sCR at day 100 with MRD negativity • Len maintenance x 2.5 y--> biochemical progression • KRD with PR; Goes 18 months but then presents with new bone lesions • Starts DRD→ Stable x 12 months but then presents wit new anemia. BM with 70% plasma cells and clonal evolution (-16) Now what?? Thank you! nina.shah@ucsf.edu 9 6/18/2018 Smoldering Myeloma Irene Ghobrial, MD Associate Professor of Medicine Harvard Medical School Dana Farber Cancer Institute Boston, MA Is it time to treat patients with Smoldering MM Ductal Carcinoma in Situ Metastatic breast cancer Treat as early as possible CURE Watch and wait until end organ damage NO CURE MGUS Multiple Myeloma Which patient population to consider for SMM? Probability of Progression (%) 100 Smoldering MM MGUS 80 60 51 27% will convert in 15 years Roughly 2% per year 78 73 66 27% more will convert in remaining 15 yrs ~ 2% per yr 40 51% will convert in first 5 yrs ~ 10% per yr 20 4 0 0 5 10 21 16 10 15 20 25 Yrs Since Diagnosis Kyle R. N Engl J Med 2007; 356:2582-90; Greipp RR, et al. J Clin Oncol 2005;23:3412–3420 1 6/18/2018 What is the definition of MM or SMM? Rajkumar et al. Lancet Oncology 2014; 15: e538-48 What is high risk SMM? Identification of high-risk SMM 50% of progression risk at 2y • Mayo Clinic: ≥10% clonal plasma cell bone marrow infiltration, and ≥30g/L of serum M-protein, and serum-free light ratio >0.125 or <8 • Spanish: ≥95% of aberrant plasma cells measured by flow plus >25% decrease in one or both uninvolved immunoglobulins • Heidelberg: Tumor mass defined by Mayo risk model plus t(4;14)/del17p/gains of 1q/ • Japanese: Beta 2-microglobulin ≥ 2.5 mg/L plus M-protein increment rate > 1 mg/dL/day • SWOG: serum M-protein ≥2 g/dL plus involved free light chain >25 and GEP >-0.26 (71% of risk progression at 2 yrs) • PENN: ≥ 40% clonal PCBM infiltration plus sFLC ratio ≥ 50 plus Albumin 3.5 mg/dL (81% of risk at 2 yrs • Czech & Heidelberg: immunoparesis plus serum M-protein ≥ 2.3 g/dL plus involved/uninvolved sFLC > 30 (81% of risk at 2 yrs) • Barcelona: evolving pattern plus serum M-protein ≥ 3 g/dL plus immunoparesis (80% of risk at 2 yrs) Mayo Clinic model: serum immunoglobulin free-light chain (FLC) ratio (n:273) PCsBM Infiltration ≥ 10% Serum M protein ≥ 3 g/dL Serum FLC ratio <1/8 or >8 Dispenzieri A. Blood 2008; 111:785-9 2 6/18/2018 Evolution pattern of the M-spike: evolving vs nonevolving (n:207) Evolving SMM (52 (25%)): at least 10% increase within the first 6 months from diagnosis when M-Protein was ≥30 g/L or progressive increase in M-Protein in each of the annual consecutive measurements during a period of 3 years in patients with an initial MP < 30 g/L Non-evolving (75%): Stable serum M-protein until progression occurs Median TTP 3 years Evolving SMM • Risk progression at 2 years: 45% Mediana TTP 19,4 years p < 0,001 • Risk progression at 5 years: 78% • IgA isotype: (41,2% frente a 23,8%, p=0,02) Fernández Larrea C et al. ASH 2014 Which patient population to consider for high risk SMM? Each model appears to identify patients at high risk, with some but not complete overlap Bone marrow clonal plasma cells ≥10% and any one or more of the following: • Serum M protein ≥3.0gm/dL • IgA SMM • Immunoparesis with reduction of two uninvolved immunoglobulin isotypes • Serum involved/uninvolved free light chain ratio ≥8 (but less than 100) • Progressive increase in M protein level (Evolving type of SMM)† • Bone marrow clonal plasma cells 50-60% • Abnormal plasma cell immunophenotype (≥95% of bone marrow plasma cells are clonal) and reduction of one or more uninvolved immunoglobulin isotypes • t (4;14) or del 17p or 1q gain • Increased circulating plasma cells • MRI with diffuse abnormalities or 1 focal lesion (≥5mm) • PET-CT with one focal lesion (≥5mm) with increased uptake without underlying osteolytic bone destruction • Monoclonal light chain excretion of 500mg/24 hours or higher Rajkumar et al, Blood 2015 Should we consider therapeutic interventions in SMM Manier, Salem, et al. Nat Rev Clin Oncol, 2016 3 6/18/2018 Should we use single agents or combination therapy to treat high-risk SMM Whole-exome and targeted sequencing of SMM BM samples Genomic profile of high risk SMM indicates that it is similar to overt MM A. B. C. Non-progressors 26 Progressors - 37 D. Bustoros et al, Unpublished data Treatment goals for high-risk smouldering myeloma Landgren et al, Clin Cancer Research 2011 Early Therapeutic Intervention Mateos MV, et al. NEJM 2013 Mateos MV, et al. Lancet Oncology 2016 4 6/18/2018 Phase II trial of Elotuzumab/Len/Dex in high risk SMM Stem Cell Mobilization and Collection Arm A 2 Months 6 Months Elotuzumab Days 1, 8, 15, 22 16 Months Elotuzumab Days 1, 15 Revlimid Days 1-21 Revlimid Days 1-21 Decadron Days 1, 8, 15, 22 Decadron Days 1, 8, 15 Elotuzumab Day 1 Revlimid Days 1-21 End of Treatment Event Monitoring (Up to 3 years) As of 08/14/2015 11 patients were enrolled on Arm B (Elotuzumab amended to Event End of enrollment to Arm Monitoring Elotuzumab Days 1, 15 A (Elotuzumab, Elotuzumab Day 1Revlimid, and Treatment Dexamethasone) and halt Arm Revlimid Days 1-21 enrollment Revlimidto Days 1-21 B . To date, 40 patients (Up to 3 years) have been enrolled on Arm A. and Revlimid). As of 1/15/16, the protocol was 2 Months 6 Months 16 Months Elotuzumab Days 1, 8, continue 15, 22 Revlimid Days 1-21 Arm B Stem Cell Mobilization and Collection Ghobrial I, et al. ASH 2016. Abstract 976 GEM-CESAR: Study Design • Multicenter, open-label, phase II trial Consolidation 2 x 28-day cycles Induction 6 x 28-day cycles High-risk* Smouldering MM patients N=90 Carfilzomib i.v. 20/36 mg/m2 Days 1, 2, 8, 9, 15, 16 Lenalidomide 25 mg Days 1–21 High-dose Melphalan [200 mg/m2] Followed by ASCT Dexamethasone 40 mg Days 1, 8, 15 & 22 Carfilzomib i.v. 20/36 mg/m2 Days 1, 2, 8, 9, 15, 16 Lenalidomide 25 mg Days 1–21 Dexamethasone 40 mg Days 1, 8, 15 & 22 Maintenance 24 x 28-day cycles Lenalidomide 10 mg Days 1–21 Dexamethaso ne 20 mg Days 1, 8, 15 & 22 *High-risk was defined according to the Mayo and/or Spanish models - Patients with any one or more of the biomarkers predicting imminent risk of progression to MM were allowed to be included but… - New imaging assessments were mandatory at screening and if bone disease was detected by CT or PET-CT, patients were excluded Mateos MV, et al. ASH 2017, abstract 402 Current Studies in High-Risk Smoldering MM • Lenalidomide or observation (phase III)1 • Ixazomib + lenalidomide + dexamethasone (phase II)2 • Isatuximab (phase II)3 • Daratumumab single agent at different doses (Centaurus trial)4 • Dara ph II for high-risk MGUS and low-risk smoldering5 • Randomized Ph III AQUILA (sc)6 Recruitment status: Recruiting Start date: November 2017 Estimated completion date: December 2025 1. ClinicalTrials.gov. NCT01169337. 2. ClinicalTrials.gov. NCT02916771. 3. ClinicalTrials.gov. NCT02960555. 4. Hofmeister CC, et al. Blood 2017 130:510 5. ClinicalTrials.gov. NCT03236428. 6. ClinicalTrials.gov. NCT03301220. 5 6/18/2018 Center for Prevention of Progression of Blood Cancers www.dana-farber.org/cpop PCROWD Retrospective Studies Therapeutic Biology Screening pcrowd.dana-farber.org/ Predicting progression of developing Myeloma in a High-Risk screened population (PROMISE) 6 6/18/2018 http://ghobriallab.danafarberdev.org/ Aldo Roccaro, Salomon Manier, Jihye Park, Antonio Sacco, Yujia Shi, Yuji Mishima, Oksana Zavidij, Marzia Capelletti, Daisy Huynh, Karma Salem, Yawara Kawano, Sioban Glavey , Jiantao Shi, Michele Moschetta, Adriana Perilla-Glen, Patrick Henrick, Kim Noonan, Kaitlen Reyes,, Joe Cappuccio, Aaron Caola. Gad Getz, Viktor Adelsteinsson, Ken Anderson, Rob Soiffer, Nikhil Munshi, Paul Richardson, Ben Ebert. Other collaborators: David Scadden, Shaji Kumar, Ola Landgren, Antonio Palumbo, Herve Ave L’oiseau, Xavier Leleu,, Leif Bergsagel, Marta Chesi, Bruno Paiva, Jesus San Miguel, Richard Hynes, George Daley, Jon Licht, Gad Getz, David Root. Viktor Adalsteinsson 7
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