Multiple Myeloma New Trials and New Drugs. Rafat Abonour, M.D.

Transcription

1 Multiple Myeloma New Trials and New Drugs Rafat Abonour, M.D.

2 Treatment Combinations Then and Now NEW VD Rev/Dex CyBorD VTD VRD CDR SCT VD/VRD Lenalidomide Bortezomib Bortezomib Lenalidomide Thalidomide Carfilzomib Pomalidomide Dratumumab Elotuzumab HDAC Bendamustine Front line treatment Maintenance Relapsed Induction Consolidation Post consolidation Rescue OLD Thal/Dex VAD DEX SCT Nothing Prednisone Thalidomide Few options

3 Achieving Great cytoreduction ( VGPR/CR) = Better Outcomes Probability of OS Probability of OS 1. Achieving VGPR 1 Achieving CR P = CR + VGPR (n = 445) PR (n = 288) Time Since Transplantation, years.2 CR or better VGPR PR SD PD Time Since Transplantation, years 1. Harousseau JL, et al. J Clin Oncol. 29;27: Kapoor P, et al. J Clin Oncol. 213;31:

4 Depth of Response Influence Time to Progression

5 Is three better than two?

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9 The New Kid on the Block :Carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (DEX) AJ Jakubowiak, 1 K Griffith, 2 D Dytfeld, 3 DH Vesole, 4 S Jagannath, 5 T Anderson, 2 B Nordgren, 2 K Detweiler-Short, 2 D Lebovic, 2 K Stockerl-Goldstein, 6 T Jobkar, 2 S Wear, 7 A Al-Zoubi, 2 A Ahmed, 2 M Mietzel, 2 D Couriel, 2 M Kaminski, 2 M Hussein, 8 H Yeganegi, 9 R Vij 6 1 University of Chicago, Chicago, IL; 2 University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; 3 Poznan University of Medical Sciences, Poznan, Poland; 4 John Theurer Cancer Center, Hackensack, NJ; 5 Mount Sinai Medical Center, New York, NY; 6 Washington University School of Medicine, St. Louis, MO; 7 Multiple Myeloma Research Consortium, Norwalk, CT; 8 Celgene, Inc, Summit, NJ; 9 Onyx Pharmaceuticals, South San Francisco, CA

10 Treatment Roadmap Transplanteligible and - -ineligible patients CRd Induction CRd Cycles 1 4 CRd Cycles 5 8 Transplant-eligible PR ASCT Stem cell collection CRd Maintenance CRd Cycles 9 24 Lenalidomide (off protocol) LEN Cycles 25+ Until disease progression or unacceptable toxicity Assessments on D1 and 15 of C1 and D1 thereafter using modified IMWG Criteria with ncr Cycles 1 8 CFZ Days 1 2, 8 9, at assigned doses 1 LEN 25 mg Days 1 21 DEX 4 mg weekly Cycles 1-4, 2 mg weekly Cycles 5 8 Cycles 9 24 CFZ on Days 1 2 and only CFZ, LEN, DEX at last best tolerated doses After Cycle 4, pts could undergo stem cell collection and then continue CRd with the option to proceed to ASCT 1. Jakubowiak AJ, et al. Blood. 211;118: abstract

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13 Multiple Myeloma Treatment of Relapse Patients

14 First Oral PI: IXAZOMIB TOURMALINE-MM1 Study Design 28-day cycles Randomization N=722 Stratification: Number of prior therapies PI exposure ISS stage IRd Ixazomib 4 mg Days 1, 8, 15 Lenalidomide 25 mg Days 1 21 Dexamethasone 4 mg Days 1, 8, 15, 22 Rd Lenalidomide 25 mg Days 1 21 Dexamethasone 4 mg Days 1, 8, 15, 22 LEN NAÏVE OR LEN SENSITIVE Moreau P et al. N Engl J Med. 216 Apr 28;374(17): doi: 1.156/NEJM 22

15 TOURMALINE-MM1 Results I-Rd (n=36) Rd (n=362) HR P Value Median PFS, mos ORR, % VGPR, % AEs, % G3 Diarrhea 6 2 G3 PN 2 2 Benefit with IRd was also noted in pts with high-risk cytogenetics. Moreau P et al. N Engl J Med. 216 Apr 28;374(17): doi: 1.156/NEJM. 23

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18 ORR, % Daratumumab- Single Agent Efficacy in Combined Analysis PR VGPR CR scr ORR = 31% 2% 1% 3% CR or better 13% 1% VGPR or better % 5 16 mg/kg N = 148 ORR was consistent in subgroups including age, number of prior lines of therapy, refractory status, or renal function 18

19 Daratumumab Combination: Study Design Key eligibility criteria RRMM Multicenter, randomized (1:1), open-label, active-controlled, phase 3 study 1 prior line of therapy Prior lenalidomide exposure, but not refractory Creatinine clearance 3 ml/min Stratification factors No. of prior lines of therapy ISS stage at study entry Prior lenalidomide R A N D O M I Z E 1:1 DRd (n = 286) Daratumumab 16 mg/kg IV Qw in Cycles 1 to 2, q2w in Cycles 3 to 6, then q4w until PD R 25 mg PO Days 1 to 21 of each cycle until PD d 4 mg PO 4 mg weekly until PD Rd (n = 283) R 25 mg PO Days 1 to 21 of each cycle until PD d 4 mg PO 4 mg weekly until PD Cycles: 28 days Primary endpoint PFS Secondary endpoints TTP OS ORR, VGPR, CR MRD Pre-medication for the DRd treatment group consisted of dexamethasone 2 mg, a acetaminophen, and an antihistamine Time to response Duration of response Statistical analyses Primary analysis: ~177 PFS events ISS, international staging system; DRd, daratumumab/lenalidomide/dexamethasone; IV, intravenous; qw, weekly; q2w, every 2 weeks; q4w, every 4 weeks; PD, progressive disease; R, lenalidomide; PO, oral; d, dexamethasone; Rd, lenalidomide/dexamethasone; PFS, progression-free survival; TTP, time to progression; OS, overall survival; ORR, overall response rate; VGPR, very good partial response; CR, complete response; MRD, minimal residual disease. a On daratumumab dosing days, dexamethasone 2 mg was administered as pre-medication on Day 1 and Day 2. 19

20 Characteristic Age, y Median (range) 75, % ISS stage, % a I II III Median (range) time from diagnosis, y Creatinine clearance (ml/min), % N >3-6 >6 Cytogenetic profile, (%) b N Standard risk High risk Baseline Demographic and Clinical Characteristics DRd (n = 286) 65 (34-89) (.4-27.) Rd (n = 283) 65 (42-87) ( ) Characteristic Prior lines of therapy, % Median (range) >3 1-3 c DRd (n = 286) 1 (1-11) Rd (n = 283) 1 (1-8) Prior ASCT, % Prior PI, % Prior bortezomib, % Prior IMiD, % Prior lenalidomide, % Prior PI + IMiD, % Refractory to bortezomib, % Refractory to last line of therapy, % ASCT, autologous stem cell transplantation; PI, proteasome inhibitor; IMiD, immunomodulatory drug. a ISS staging is derived based on the combination of serum β2-microglobulin and albumin. b Central next-generation sequencing. High-risk patients had any of t(4;14), t(14;16), or del17p. Standard-risk patients had an absence of high-risk abnormalities. c Exploratory. 2

21 % surviving without progression ORR, % Updated Efficacy month PFS a 76% Median: not reached DRd ORR = 93% 23 P <.1 ORR = 76% HR:.37 (95% CI,.28-.5; P <.1) 49% Rd Median: 17.5 months CR: 46% b VGPR: 78% b CR: 2% DRd (n = 281) Rd (n = 276) VGPR: 45% scr CR VGPR PR No. at risk Months Rd DRd Median (range) follow-up: 17.3 (-24.5) months Responses continue to deepen in the DRd group with longer follow-up HR, hazard ratio; CI, confidence interval; scr, stringent complete response; PR, partial response. Note: PFS = ITT population; ORR = response-evaluable population. a Kaplan-Meier estimate; b P <.1 for DRd vs Rd. 21

22 MRD-negative rate, % MRD-negative Rate ,8 * * * 3.6X 4.4X 4.8X * P < , ,9 1 8,8 5 5,7 2,5 Sensitivity DRd Rd DRd Rd DRd Rd threshold MRD-negative rates were >3-fold higher at all thresholds Intent-to-treat population. P values are calculated using likelihood-ratio chi-square test. 22

23 % surviving without progression PFS: Cytogenetic Risk in All Evaluable Patients a Comparable results in 1 to 3 prior lines population No. at risk Rd std risk DRd std risk Rd high risk DRd high risk Months DRd standard risk DRd high risk Rd standard risk Rd high risk High risk Standard risk Median PFS, mo HR (95% CI) P value ORR, % P value DRd n = 28 DRd n = 133 Rd n = 113 NR ( ) <.1 n = 132 n = Rd n = 37 Median PFS, mo NR 1.2 HR (95% CI) P value.44 ( ).475 ORR, % P value n = 27 n = 36 NS DRd improves outcomes regardless of cytogenetic risk NR, not reached; NS, not significant. a ITT/Biomarker risk evaluable analysis set. High-risk patients had any of t(4;14), t(14;16), or del17p. Standard-risk patients had an absence of high-risk abnormalities. 23

24 % surviving patients OS 1 8 DRd Rd OS events a 6 4 (14%) in DRd 56 (2%) in Rd 4 2 HR:.63 (95% CI: ) No. at risk Months Rd DRd Curves are beginning to separate, but OS data are immature Intent-to-treat population. Median OS was not reached; results did not cross the prespecified stopping boundary. 24

25 CAR T Immune Therapy 29

26 T cells CAR-T are white blood cell cells therapy that attack and 11 kill viruses and cancer cells I hope Chimeric antigen receptors (CARs) help T-cells recognize and destroy cancer cells 1. T cells are collected from the patient. A machine removes the desired cells from the blood, then returns the rest back to the patient. 3

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28 CAR-BCMA T Cells in Myeloma: Background T cells can be genetically modified to express chimeric antigen receptors (CARs) specific for malignancy-associated antigens B-cell maturation antigen (BCMA) is expressed by normal and malignant plasma cells. BCMA is a potential target for CAR T-cell therapy for MM T Cell AntiBCMA T Cell AntiBCMA T Cell AntiBCMA T Cell AntiBCMA The patient s own T-cells were stimulated, transduced with CAR-BCMA retroviruses, and cultured for 9 days before infusion. Study presented ASH 215 evaluated CAR- BCMA T cell infusion for treatment of advanced MM 1. Carpenter RO, et al. Clin Cancer Res. 213;19: Ali SA, et al. ASH 215. Abstract LBA-1. 31

29 CAR-BCMA T Cells in Myeloma: Study Design First-in-human phase I trial Pts with advanced relapsed/ refractory MM More than 3 prior lines of therapy; BCMA expression on myeloma cells 12 patients enrolled Cyclophosphamide 3 mg/m 2 Fludarabine 3 mg/m 2 QD for 3 days CAR-BCMA T cells* Single infusion *Dose escalation of CAR+ T cells/kg.3 x x x x 1 6 Ali SA, et al. ASH 215. Abstract LBA-1. 32

30 CAR-BCMA T Cells in Myeloma: Response to therapy Response to Therapy Stringent complete response(scr) Number of Patients (total 12 treated) 1 Very good partial response VGPR 1 Partial response 2 Stable disease 8 Ali SA et al. Proc ASH 215;Abstract LBA1. 33

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32 Bortezomib + AIDS drug (Nelfinavir) St Gallen team from Switzerland. 34 patients resistant to Bortezomib (velcade). Nelfinavir and oral (HIV protease inhibitor) Nelfinavir and bortezomib was well tolerated Overall response rate was 65%. Four patients achieved very good partial response. ASH 216 abstract 487.

33 Venetoclax Monotherapy for Relapsed/ Refractory Multiple Myeloma: Safety and Efficacy Results From a Phase I Study Shaji Kumar, 1 Ravi Vij, 2 Jonathan L Kaufman, 3 Joseph Mikhael, 4 Thierry Facon, 5 Brigitte Pegourie, 6 Lofti Benboubker, 7 Cristina Gasparetto, 8 Martine Amiot, 9 Philippe Moreau, 9 Stefanie Alzate, 1 Jeremy Ross, 1 Martin Dunbar, 1 Tu Xu, 1 Suresh Agarwal, 1 Joel Leverson, 1 Paulo Maciag, 1 Maria Verdugo, 1 Cyrille Touzeau 9 1 Mayo Clinic, Rochester, MN, USA; 2 Washington University School of Medicine, St. Louis, MO, USA; 3 Winship Cancer Institute of Emory University, Atlanta, GA, USA; 4 Mayo Clinic, Scottsdale, AZ, USA; 5 CHRU Lille, Hopital Huriez, France; 6 CHU Grenoble, France; 7 CHRU Tours, France; 8 Duke University, Hematologic Malignancies & Cellular Therapy, Durham, NC, USA; 9 CHU de Nantes, Hotel Dieu HME, France; 1 AbbVie Inc., North Chicago, IL, USA American Society of Hematology 58 th Annual Meeting San Diego, California, USA December 4, 216

34 Background Anti-apoptotic proteins BCL- 2 and MCL-1 promote multiple myeloma (MM) cell survival 1 Venetoclax induces cell death in multiple myeloma (MM) cell lines and primary samples, particularly those positive for the translocation t(11;14), which correlates with higher ratios of BCL2 to MCL1 and BCL2 to BCL2L1 (BCL-X L ) mrna 1,2 1. Touzeau C et al. Leukemia Punnoose E et al. Mol Cancer Ther

35 Patient Disposition Enrolled Time on study, median (range), months Time on venetoclax monotherapy, median (range), months Time on venetoclax + dexamethasone, a median (range), months All Patients (.2 27) 2.5 (.2 25) 1.4 (.1 13) Active, n (%) 11 (17) Discontinued, n (%) 55 (83) Primary reason for discontinuation, n (%) Related to disease progression Adverse events Withdrawn consent Lost to follow up Reason not specified 41 (62) 5 b (8) 2 (3) 1 (2) 6 (9) Deaths, n (%) 8 c (12) a n=17 received combination therapy; dexamethasone was added after disease progression. b Renal failure (2), worsening pulmonary disorder (1), paralyzing sciatica (1), and shortness Data cutoff of 19Aug216 35

36 P e rc e n ta g e o f P a tie n ts Objective Response Rates in all Patients and by t(11;14) Status 5 s C R C R V G P R P R N t(1 1 ;1 4 ) M M 3 4 O R R 4 % 4% R e fr a c t o r y t o : L a st l i n e o f th e ra p y B o rte z o m i b (B O R T ) L e n a l i d o m i d e (L E N ) % C a rfi l z o m i b (C A R F ) P o m a l i d o m i d e (P O M ) B O R T / L E N O R R 2 1 % B O R T / C A R F B O R T / P O M % 4% 8% 6% A ll P a t ie n t s N = % 1 3 % t( 1 1 ; 1 4 ) n = 3 O R R 6 % 3% 3% n o n - t ( 1 1 ; 1 4 ) n = 3 6 L E N / C A R F L E N / P O M C A R F / P O M B O R T / L E N / C A R F B O R T / L E N / P O M B O R T / C A R F / P O M L E N / C A R F / P O M B O R T / L E N / C A R F / P O M O v e r a ll r e s p o n s e r a te (% ) Data cutoff of 19Aug216 36

37 n o n -t(1 1 ;1 4 ) t(1 1 ;1 4 ) Current Status on Study O R R s C R /C R V G P R P R M R S D P D s C R V G P R S D * P D * * T im e o n s tu d y, m o n th s V e n e to c la x m o n o th e r a p y (t[1 1 ;1 4 ]) V e n e to c la x m o n o th e ra p y (n o n -t[1 1 ;1 4 ]) V e n e to c la x + D e x a m e th a s o n e *Patient discontinued with no response data; Patient discontinuation was related to progression. Data cutoff of 19Aug216 37

38 P e rc e n ta g e o f P a tie n ts % N o t P ro g r e s s e d Responses by BCL2:BCL2L1 Ratio Among t(11;14)-positive Patients s C R C R V G P R P R O R R 8 8 % 1 1 % 1 T im e to P r o g r e s s io n B C L 2 Gene :B C L 2expression L 1 ra tio a m oratio n g among t(11;14) patients p a tie n ts w ith t(1 1 ;1 4 ) % 7 5 High BCL2:BCL2L1 F a v o ra b le N Low o n -fa BCL2:BCL2L1 v o ra b le % % BCL2:BCL2L1 (BCL-X L ) F a v o r a b l e (n=9) n = 9 O R R 2 % 1 3 % 7% High Low B C L 2 :B C L 2 L 1 r a tio fo r P a tie n ts w ith t(1 1 ;1 4 ) BCL2:BCL2L1 N o n - f a v o r a b l e n (n=15) = M o n th s s in c e firs t d o s e N o. a t ris k N o. a t ris k BCL2 and BCL2L1 (BCL-X L ) quantitation using droplet digital PCR performed on CD138-selected bone marrow mononuclear cells collected at baseline. Bootstrapping and Aggregating Thresholds from Trees (BATTing) used to estimate threshold BCL2:BCL2L1 for selection of patients likely to have a clinical response vs non-response. Data cutoff of 19Aug216 38

39 Nivolumab + donor lymphocyte infusion

40 Conclusions Survival is improving due to better combinations and leading to robust eradication of myeloma burden. Combination therapy provide higher rates of negative minimal residual disease results and improve survival. Immune therapy is very promising. Newer drugs are very encouraging.