Conflict of Interest Disclosure Form

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1 Conflict of Interest Disclosure Form NAME : Niels van de Donk MD-PhD AFFILIATION: University of California San Francisco. In accordance with the rules of the Health Care Inspectorate (IGZ), speakers are required to fill out a disclosure statement. Please fill out the disclosure form. Only after completion you are able to submit the abstract and allowed to give your presentation. You are obliged to start your presentation with this disclosure statement. DISCLOSURE I have no potential conflict of interest to report X I have the following potential conflict(s) of interest to report Type of affiliation / financial interest Receipt of grants/research supports: Receipt of honoraria or consultation fees: Name of commercial company Celgene, Janssen, BMS, Novartis, AMGEN Celgene, Janssen, BMS, Novartis, AMGEN Participation in a company sponsored speaker s bureau: -- Stock shareholder: -- Other support (please specify): -- Scientific advisory board -- HOVON NVvH Dutch Hematology Congress, congress bureau, VU medical centre PK 5 X 172, De Boelelaan HV Amsterdam

2 HOVON EDUCATIONAL MYELOOM Case 3: double-refractory MM NIELS VAN DE DONK Department of Hematology, Amsterdam, Netherlands Amsterdam, Netherlands

3 Case 3 27 Multipel myeloom, IgG-kappa Treatment: HOVON65: 3 xvad HDM+auto-SCT August 21 Progression, bortezomib-dexamethasone PR March 211 Progression, lenalidomide-dexamethasone PR Jan 212 Progression, thalidomide-dexamethasone, MR Jan 213 Progression during thalidomide-dexamethasone NOW: BORTEZOMIB and LENALIDOMIDE/THALIDOMIDErefractory MM

4 QUESTION 1 Overall survival? 1) 3 months 2) 9 months 3) 14 months 4) 24 months

5 Patients who are refractory to bortezomib and IMiDs have a poor prognosis 1 8 Survival Outcomes Events/N Median (range), Months Overall survival 17/286 9 (7-11) Event-free survival 217/286 5 (4-6) Patients, % Duration From Time Zero, months Thus, a great need remains for agents with new MoAs for Kumar Leukemia 212 relapsed/refractory patients 4

6 Decreasing response duration with increasing number of salvage regimens Cumulative Probability Overall Survival by Line of Therapy 2 Regimen First Second Third Fourth Fifth Sixth Years from Initiation of Regimen Kumar Mayo Clin Proceed 24

7 Factors influencing choice of therapy at relapse Tumour features Extramedullary disease Rapid increase in tumour load/ bone lesions Chromosomal abnormalities Variations in tumour cell gene expression profiles Host features Performance status Age Bone marrow reserve Comorbidities (renal function, DVT, PNP) Germline variation affecting microenvironment, apoptosis/proliferation, immune status, drug metabolism/transport, and DNA repair Treatment Time from prior therapy Response to prior therapies DVT, deep-vein thrombosis; PNP, peripheral neuropathy. van de Donk NW, et al. Cancer Treat Rev. 211;37: Amsterdam, Netherlands

8 Case 3 Jan 213 BORTEZOMIB and LENALIDOMIDE/THALIDOMIDE-refractory MM start daratumumab in GEN51 study Minimal response, duration of 1 months, no adverse events

9 DARATUMUMAB Van De Donk Blood 215

10 DARA: Mechanisms of Action CD38 is highly and ubiquitously expressed on myeloma cells 1,2 DARA DARA is a human IgG1 monoclonal antibody that binds CD38-expressing cells DARA binding to CD38 induces tumor cell death through direct and indirect mechanisms 3-5 Immune-mediated activity CDC Complement ADCP Macrophage ADCC NK cell Direct anti-tumor effect Apoptosis via cross-linking Decreased immunosuppression Immunomodulation CD38 enzymatic inhibition CD38 MM cell DARA CD38 + T reg CD8 + T cell CD38 DARA MM cell NAD cadpr ADPR Ca 2+ AMP NAADP Ca 2+ Ca 2+ Ca 2+ Adenosine Adenosine Tumor cell death CD38 MDSC B reg CD38 Krejcek ASH 215 Abstract 337 9

11 Daratumumab: waterfall plot 16 mg/kg: ORR 35% Lokhorst NEJM 215

12 Daratumumab monotherapy: Progression-free Survival Patients progression-free and alive, % Responders MR/SD PD/NE Responders: NE (7.4, NE) MR/SD: 3.2 ( ) months PD/NE:.9 (.9-1.) months Patients at risk Responders MR/SD PD/NE Time from first dose, months Usmani ASH 215 Abstract 29; Lokhorst NEJM 215; Lonial Lancet

13 Daratumumab monotherapy: Overall Survival 1 Patients alive, % 75 5 Responders: NE (19.9, NE) MR/SD: 17.5 (15.1-NE) months 25 PD/NE: 3.7 ( ) months 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 (95% CI, 15.1-NE) months 1-year overall survival rate = 69% (95% CI, ) Usmani ASH 215 Abstract 29; Lokhorst NEJM VU 215; University Lonial Lancet Medical 216 Center 12

14 RICHTLIJN DARA monotherapie: Lenalidomide en bortezomib-refractaire ziekte Na (toevoegen van) alkylerende therapie (aan reeds voorgeschreven therapie) Maart 217 commercieel verkrijgbaar

15 Case 3 Jan 213 BORTEZOMIB and LENALIDOMIDE/THALIDOMIDE-refractory MM start daratumumab in GEN51 study Nov 213 progression during DARA What now?

16 Synergistic combinations IMID or PI/cyclophosphamide-combination Len-cyclo-pred (REP) Pom-cyclo-pred; Pom-cyclo-dexa IMID/PI-combination VTD RVD Pom-Bort-Dex (PVD) Car-Pom-Dex Pano-VD Richardson ASH ; Mikhael ASH ; Richardson Blood ; Richardson JCO ; Jimenez-Zepeda Leuk Lymph ; Larocca Blood ; Richardson ASH ; San Miguel Lancet Oncol 214

17 REP Lenalidomide 25 mg low-dose oral cyclophosphamide 5 mg prednison 2 mg Nijhof Blood 216

18 REP Median PFS: 12.1 months; Median OS: 29. months Nijhof Blood 216

19 Case 3 Jan 213 BORTEZOMIB and LENALIDOMIDE/THALIDOMIDErefractory MM start daratumumab in GEN51 study Nov 213 REP Dec 215 progression during REP, start VCD (RETREATMENT) May 216 progression What now?

20 Case 3 BORTEZOMIB and LENALIDOMIDE/THALIDOMIDErefractory MM Also alkylator-refractory disease WHAT NOW? THERAPY OPTIONS: -1) pomalidomide-dexamethasone -2) carfilzomib -3) daratumumab monotherapie [retreatment] -4) study -5) other

21 Case 3 QUESTION 2 THERAPY OPTIONS: -1) pomalidomide-dexamethasone -2) carfilzomib -3) daratumumab monotherapie [retreatment] -4) study -5) other

22 MM-3 Design POM + LoDEX vs. HiDEX Heavily pretreated (5 median lines of therapy), all patients received bortezomib and lenalidomide previously 75% double refractory RANDOMIZATION 2:1 (n = 32) POM: 4 mg/day D LoDEX: 4 mg ( 75 yrs) 2 mg (> 75 yrs) D1, 8, 15, 22 HiDEX: 28-day cycles (n = 153) 4 mg ( 75 yrs) 2 mg (> 75 yrs) D1-4, 9-12, 17-2 PD a or Unacceptable AE PD a or Unacceptable AE Thromboprophylaxis was required for those receiving POM or at high risk for DVT Follow-Up for OS and SPM Until 5 Years Post Enrollment Companion trial MM-3C POM 21/28 days San-Miguel et al Lancet Oncology 213;14(11):155-66

23 Pomalidomide and low dose Dex resulted in superior PFS and OS independent of being double refractory 1. POM + LoDEX (N = 32) Median PFS 4. mos 1. POM + LoDEX (N = 32) Median OS 13,1 mos Proportion of Patients HiDEX (N = 153) HR =.5 P < mos 2 24 Proportion of Patients HiDEX (N = 153) HR =.72 P =.9 After adjusting for crossover the difference in OS was 7months 8.1 mos Months Months San-Miguel et al Lancet Oncology 213;14(11):155-66

24 RICHTLIJN Pomalidomide-dexamethason Lenalidomide en bortezomib-refractaire ziekte Na (toevoegen van) alkylerende therapie (aan reeds voorgeschreven therapie)

25 HOW TO IMPROVE?

26 MM1 Durvalumab=anti-PD-L1 Durvalumab + pomalidomide -> Durvalumab + pomalidomide + dexamethasone NB pomalidomide als anti-tumor middel EN als immuun stimulator

27

28

29 Myeloom: rem op de T cel T cel MM cel

30 PD-L1 downregulates cytotocix T-cell activity to maintain immune homeostasis MM cell

31 PD-L1 downregulates cytotocix T-cell activity to maintain immune homeostasis MM cell

32 PD-L1 downregulates cytotocix T-cell activity to maintain immune homeostasis MM cell

33 Case 3 June 216: start DURVALUMAB-POMA-DEXA in MM-1 study VGPR, continued response till now adverse events: neuropathy for which dose reduction POMA

34 How to improve the efficacy of pomalidomide-dexamethasone?

35 Combinations with Pomalidomide At least 2 prior lines Len-refractory Phase 2: Pom-Dex vs Pom-Cyclo-Dex (n=36/34) prior lines Len-refractory Phase 2: Pom-Bortez-Dex (n=47) 2 PD PCD p PVD ORR, % VGPR, % NA 45 PFS, months OS, months 16.8 Not reached.138 EFS of 94% at 12m 1.Baz et al. ASH 214 (Abstract 33), oral presentation 2.Lacy et al. ASH 214 (Abstract 34), oral presentation

36 Regimen Other available combinations: Pom/dex combinations K + POMdex 2 Ixa + POMdex 3 Carfilzomib 2/27/36 mg/m 2 D1,2,15,16 + POM 3 or 4 mg/day D Dex QW 4 mg C1 4 (2 mg C5 8) (n=46) The same combination but K weekly (n=57) Ixazomib 3 or 4 mg D1,8,15 + POM 4 mg/day D Dex 4 mg D1,8,15,22 (>75 y: 2 mg) (All, n=32; Ixa 4 mg, n=25) Study phase 1/2 1/2 Prior lines of therapy, n Refractory to Len, n (%) Refractory to PI, n (%) 1 5 including PI and Len 4 (87)/41(72) 32 (1); 25 (1) NR 2 (63); 15 (6)* ORR, % 64/64 44 Median (range) DOR NR 56 (28-16) months Median PFS, months 12.9/9.2 NR 1.Richardson et al. Presented at EHA 216; P653; 2. Rosenbaum et al. Presented at ASH 215 (Abstract 87); 3. Krishnan et al. Presented at ASCO 216 (Abstract 88), oral presentation; 4. Chari et al. Presented at ASH 215 (Abstract 58), oral presentation

37 Other available combinations: Pom/dex combinations Dara + POMdex 4 Regimen Daratumumab 16 mg/kg C1 2 QW; C3 6 Q2W; C7 13 or until PD Q4W + POM 4 mg/day D Dex 4 mg (>75 y: 2 mg) (n=98) Isa+ POMdex Isatuximab 1 mg/kg IV C1 QW; Q2W thereafter + POM 4 mg/day D Dex 4 mg (>75 y: 2 mg) (m=14) MOR22+ POMdex MOR22 at dose of 4, 8, 16 mg/kg QW + POM 4 mg/day D Dex 4 mg (>75 y: 2 mg) (n=9= Study phase 1 1/2 1/2 Prior lines of therapy, n Refractory to Len, n (%) Refractory to PI, n (%) 2 (2 13) 4.5 (3-11) 2 87 (89) 15(75) 9 (1) 74 (76) - - ORR, % Median (range) DOR NR 4 months - Median PFS, months 6-m rate = 66% Richardson et al. Presented at EHA 216; P653; 2. Rosenbaum et al. Presented at ASH 215 (Abstract 87); 3. Krishnan et al. Presented at ASCO 216 (Abstract 88), oral presentation; 4. Chari et al. Presented at ASH 215 (Abstract 58), oral presentation

38 HOW TO IMPROVE POMA-DEXA? Pomalidomide-dexamethasone +cyclophosphamide Bortezomib-pomalidomide-dexamethasone Carfilzomib-pomalidomide-dexamethasone Ixazomib-pomalidomide-dexamethasone Pomalidomide-dexamethasone +DARATUMUMAB Pomalidomide-dexamethasone +PEMBROLIZUMAB Pomalidomide-dexamethasone-NIVOLUMAB Pomalidomide-dexamethasone + DURVALUMAB (open in NL) Pomalidomide-dexamethasone + ELOTUZUMAB (open in NL)

39 Study Design Schematic Cycle 1 and 2 Cycle 3 and beyond R A N D O M I Z A TI O N Control Arm 114 Subjects (1:1) Elotuzumab Arm Pomalidomide: 4 mg PO daily (Days 1-21) of each cycle Dexamethasone: Dosing based on age 4 mg vs 2 mg (< 75 or >75 years old Days 1,8, 15, 22 Elotuzumab: 1 mg/kg IV (Days 1, 8, 15, 22) of each cycle Pomalidomide: 4 mg PO daily (Days 1-21) of each cycle Dexamethasone: 28 mg PO + 8 mg IV on days of elotuzumab dosing (subjects < 75 years old) 8 mg PO + 8 mg IV on days of elotuzumab dosing (subjects > 75 years old) Pomalidomide: 4 mg PO daily (Days 1-21) of each cycle Dexamethasone: Dosing based on age 4 mg vs 2 mg (< 75 or >75 years old Days 1,8, 15, 22 Elotuzumab: 2 mg/kg IV Day 1 of each cycle Pomalidomide: 4 mg PO daily (Days 1-21) of each cycle Dexamethasone (weeks with Elotuzumab dosing): 28 mg PO + 8 mg IV on days of elotuzumab dosing (subjects < 75 years old) 8 mg PO + 8 mg IV on days of elotuzumab dosing (subjects > 75 years old) Dexamethasone (weeks without Elotuzumab dosing: 4 mg PO per week for subjects < 75 years old 2 mg PO per week for subjects > 75 years old Follow-Up Follow-up every 4 weeks for tumor response until PD: Then survival follow-up every 12 weeks or more frequently 38

40 HOW TO IMPROVE DARA MONOTHERAPY? DARA + ATRA (IIT, open in NL) DARA+NIVOLUMAB or DARA+NIVOLUMAB+LENA+DEXA (IIT, opens Q2 217)

41 Case 3 What if our patient would relapse now? --Alkylator R --BORT R --THAL R --LEN R --POM R --DARA R OPTIONS -STUDY -CARFILZOMIB

42 Other Studies in Netherlands for relapsed/refractory MM OPEN HOVON 114 (IIT) PANORAMA 3: panobinostat + bortezomib/dexa (NOVARTIS) Subcutaneous DARA (Janssen) Haplo SCT (IIT) SOON CC-22 (Celgene) CAR T cells (Autolus) BCMA/CD3 bispecific antibody (Janssen)

43 Conclusion and Future Perspectives No uniform standard of care of treatment of refractory MM patients, but relapse treatment is individualized: type of relapse, previous therapies, co-morbidities, side-effects, etc Development of biomarkers to predict response to therapy individualized therapy Increased understanding disease biology and mechanisms of resistance new drugs with novel mechanisms of action