Multiple Myeloma What is New? Can we talk cure? Rafat Abonour, M.D.

Transcription

1 Multiple Myeloma What is New? Can we talk cure? Rafat Abonour, M.D.

2 Multiple Myeloma Facts Second most prevalent hematologic neoplasm Nearly 24, new cases diagnosed in the US per year and 11, worldwide Median age at diagnosis is 7 years Survival is increasing but cure has not been realized Based on SEER data the 5 survival of those diagnosed was only 37.1%

3 How to Overcome Multiple Myeloma Understand How Myeloma cells survive. Understand the Nature of the originating cell Understand that not all myeloma cells created equally. Understand the importance of the patients immune system

4 Myeloma Cells Like their Neighborhood Myeloma cells Tumor-derived osteoclast activating factors Macrophage inflammatory protein 1a Interleukin-3 Stromal cells RANKL (+) (+) ( ) Interleukin-6 Tumor-derived osteoblast inhibitory factors DKK1, IL3, sfrp2, IL-7, TNF Sclerostin Osteoclasts Osteoblasts Bone Activin A Osteocytes Adapted from Roodman GD. N Engl J Med. 24;35(16):

5 The Originating Cell is Stubborn myeloma stem cell Do not cycle, dormant Very drug resistant Spin off new myeloma cells

6 Clonal Heterogeneity Impacts Outcome One Nasty Disease: One Nasty Family Keats et al. Blood 212: 12: 167

7 Treatment Goals for MM Symptom Control Ameliorate pain and other disease-related symptoms Prevent further organ damage Preserve and improve performance status and quality of life Disease Response and Survival Rapid cytoreduction to relieve symptoms Minimize treatment-related toxicity and Stem Cell damamge Prolong survival Overall Survival

8 Managing myeloma: the components Transplant Eligible Patients Transplant Ineligible patients Initial Therapy Consolidation Maintenance Consolidation/ Maintenance/ Continued therapy Treatment of Relapsed disease Supportive Care

9 Treatment Combinations Now and Then 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

10 Induction Regimens Several new classes of drugs are being used in the management of multiple myeloma patients: Proteasome inhibitors Immune modulatory drugs. Monoclonal Antibodies The choice of initial induction therapy can be influenced by the underlying medical conditions of the patients and their prognostic features.

11 IMPACT OF NOVEL THERAPY 212/213 Median 7.3 years 5 YEAR SURVIVAL BY AGE AGE 65 YRS AGE > 65 YRS % 56% % 31% 212 ASH Abstract #3972 Kumar et al

12 What to Expect with Novel Combinations Prior to HD Therapy? Author (n) Regimen CR/VGPR PFS OS Cavo (236) VTD+2HD 38%/79% 68% (3 years) 86% (3 years) Moreau (1) vtd+hd 3%/73% Palumbo (12) PAD+2HD+C/ M 66%/86% 69% (2 year) 86% (2 year)* Rajkumar (9) R (D or d)+hd 92% (3 years) Harousseau (223) VD+HD 4% 68% 36 months 81% (3 years) Richardson (27) RVD+ HD 29%/67% 75% (18 mon) 97% (18 mon) N= number of subjects, Mon= month VTD Bortezomib, thalidomide and dexamethasone vtd Modified bortezomib, thalidomide and dexamethasone PAD Bortezomibe, doxirubicin and dexamethasone * age RD or Rd Lenalidomide with high dose dexamethasone (D) or low dose (d) RVD Lenalidomide Bortezomib and Dexamethasone. HD high dose chemotherapy.

13 The Overall, VGPR, and ncr/cr Rates for a Selection of Phase 2 and Phase 3 Trials Do we pick the therapy with the biggest green bar and call it a day? Stewart A K et al. Blood 29;114: by American Society of Hematology

14 Achieving Great cytoreduction ( VGPR/CR) = Better Outcomes Probability of OS Probability of OS 1. Achieving VGPR 1 Achieving CR P =.17 CR + VGPR (n = 445) PR (n = 288) Time Since Transplantation, years 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:

15 Depth of Response Influence Time to Progression

16 Patient 1- ECOG Len/ HD vs LD 5 year old man with anemia Stage II Normal cytogenetics Treated on Clinical Trial 4 Cycles Lenalidomide and high dose dexamethasone Cyclophosphamide for SC harvest High dose Melphalan

17 Patient 1- ECOG Len/ HD vs LD No additional therapy since 25 Did he achieved MDR(-)? Is he Cured?

18 Is three better than two?

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21 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

22 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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25 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

26 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 $11 k a month 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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29 MAb-Based Targeting of Myeloma Antibody-dependent cellular cytotoxicity (ADCC) ADCC Effector cells: MM FcR Complement-dependent cytotoxicity (CDC) CDC Lucatumumab or dacetuzumab (CD4) Elotuzumab (SLAM 7) Daratumumab (CD38) MOR28 (HM1.24) C1q MM Tai YT, et al. Bone Marrow Res. 211;211: Daratumumab (CD38) C1q Apoptosis/growth arrest via targeting signaling pathways MM Lorvotuzumab mertansine (CD56) nbt62-maytansinoid (CD138) 1339 (IL-6) BHQ88 (DKK1) RAP-11 (activin A) Daratumumab (CD38)

30 Targets on the Myeloma Cell Surface SLAMF7 CD38 15

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32 ORR, % Daratumumab Efficacy in Combined Analysis PR VGPR CR scr ORR = 31% 2% 1% 3% CR or better 13% 1% VGPR or better $32 k cycle1,2 $15 k cycle % 16 mg/kg N = 148 ORR was consistent in subgroups including age, number of prior lines of therapy, refractory status, or renal function 32

33 Patients progression-free and alive, % Progression-free Survival 1 75 Responders MR (Minimal Response)/SD (Stable Disease) PD (Progressive Disease)/NE (Non-Evaluable) Responders (Median ~7.4 months) 5 25 MR/SD: 3.2 ( ) months PD (median ~.9 months) Patients at risk Responders MR/SD PD/NE Time from first dose, months

34 Patients alive, % Overall Survival 1 75 Responders 5 MR/SD 25 PD Responders MR/SD PD/NE Patients at risk Responders MR/SD PD/NE Time from first dose, months For the combined analysis, median OS = 19.9 months 1-year overall survival rate = 69% (95% CI, ) 34

35 Study Design Multicenter, randomized (1:1), open-label, active-controlled, phase 3 study Key eligibility criteria RRMM 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. 35

36 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. 36

37 % 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. 37

38 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. 38

39 % progression-free and alive PFS: MRD Status (1 5 ) 1 8 Rd MRD negative (n = 16) DRd MRD negative (n = 71) 6 DRd MRD positive (n = 215) 4 Rd MRD positive (n = 267) 2 No. at risk Rd MRD negative DRd MRD negative Rd MRD positive DRd MRD positive Months MRD negativity is associated with better outcomes Intent to treat population. 39

40 % surviving without progression % surviving without progression 1 Time From Last Line of Therapy to Study Treatment of > or 12 Months >12 Months 18-month PFS a 1 12 Months 18-month PFS a 83% 8 6 6% Rd DRd 8 6 7% DRd % Median: 1.3 months 2 2 Rd HR:.37 (95% CI: ; P <.1) No. at risk Months Rd >12 DRd > HR:.38 (95% CI: ; P <.1) Months DRd is superior to Rd regardless of time since last therapy a Kaplan-Meier estimate. b Response-evaluable population. 4

41 % surviving without progression ORR, % Refractory to Last Line of Therapy 1 18-month PFS a 1 9 ORR = 87% b P = No. at risk Rd DRd Median: 1.3 months HR:.47 (95% CI: ; P =.15) 65% 36% DRd Rd Months CR: 47% c DRd (n = 78) CR: 15% VGPR: 73% c ORR = 64% b Rd (n = 73) scr CR VGPR PR VGPR: 34% DRd benefits patients refractory to last line of therapy a Kaplan-Meier estimate. b Response-evaluable population. c P <.1 for DRd vs Rd. 41

42 % 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. 42

43 % 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. 43

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53 Elotuzumab Elotuzumab (HuLuc63) is an IV humanized monoclonal antibody targeting human SLAMF7, a cell surface glycoprotein. CD16 Elotuzumab Hsi ED et al. Clin Cancer Res. 28;14: Tai YT et al. Blood. 28;112: van Rhee F et al. Mol Cancer Ther. 29;8: Lonial S et al. Blood. 29;114:432. Richardson PG, et al. ASH 214. Abstract 32 25

54 Elotuzumab is an IV humanized monoclonal antibody targeting human SLAMF7 Elotuzumab: Low single agent activity Original study with elo only in 35 pts, doses ranging from.5-2 mg/kg every two weeks demonstrated no responses but stable disease in 27% of pts However when combined with lenalidomide and dex in relapsed pts, response rate was 82% (expected would be about 6%)

55 ELOQUENT-2: Elotuzumab With Lenalidomide/Dexamethasone R/R MM Randomized, open-label, multicenter phase III trial Pts with relapsed MM and 1-3 prior treatments Elotuzumab 1 mg/kg IV QW cycles 1, 2 then Q2W + Lenalidomide 25 mg PO D Dexamethasone 4 mg PO QW (n = 321) 28-day cycles (N = 646) Lenalidomide 25 mg PO D Dexamethasone 4 mg PO QW (n = 325) Until Progression or unacceptable toxicity Primary endpoints: Progression Free time (PFS), Overall Response Secondary endpoints: Overall Survival, safety, health-related Quality of Life Dimopoulos MA, et al. ASH 215. Abstract

56 ELOQUENT-2 Results E-Rd (n=321) Rd (n=325) HR P Value Median PFS, mos <.1 ORR, % <.1 VGPR, % AEs, % G3 cardiac failure 4 6 G3 acute renal failure 4 4 No benefit observed in patients who were previously exposed to immunomodulatory agent. Patients with Del17p, 1q21 amplifications and t(4;14) faired as well as standard risk. Lonial S et al. N Engl J Med. 215;373:621.

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58 CAR T Immune Therapy 29

59 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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61 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

62 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

63 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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65 The Path to Cure Require validated minimal residual disease assessment tools and their inclusion in response criteria. Clonal heterogeneity and epigenetics need to be addressed at time of treatment selection. This may explain clonal dominance at different stages of the disease.

66 The Path to Cure We need to build a treatment program that can eradicate clonal heterogeneity and produce a negative minimal disease status. Improving immune surveillance to eradicate residual disease.