Upcoming Therapies for Myeloma in Alberta. Dr Christopher Venner Cross Cancer Institute

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1 Upcoming Therapies for Myeloma in Alberta Dr Christopher Venner Cross Cancer Institute

2 Outline Diagnosis Hope for earlier diagnosis Prognosis Update in staging system for modern era highlights clear improvements in outcomes Frontline treatment updates Transplant eligible Transplant ineligible Relapsed therapy updates 1-3 prior lines Beyond 3 lines and double exposed

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4 The Plasma Cell Bianchi and Munchi, Blood, 2015

5 Diagnostic Criteria (IMWG ) S Sixty % BMPC Li Light chain ratio > 100 M MRI lesions (>1) C - hypercalcemia R Renal failure A - Anemia B lytic Bone disease Rajkumar et al, Lancet Oncology, 2014

6 Implications for practice More tests More marrows More scans More equivocal cases

7 Prognosis Stage I: Albumin > 35 and Beta2 Microglobulin < 3.5 Stage II: Albumin < 35 or Beta2 Microglobulin Stage III: Beta2 Microglobulin > 5.5 Greipp et al, JCO 2005

8 Prognosis

9 Prognosis

10 The Canadian standard Transplant Eligible Patients CVD x 4-6 ASCT Mel200 Consolidation? Lenalidomide Maintenance Treatment of Relapsed disease Transplant Ineligible Patients CVD/VM P x 9 Bortez-based Maintenance/ continuous Tx Treatment of Relapsed disease

11 g-term follow-up data for all 63 patients treated on BorD at MCA and PMH. Eligible patients were 18 years of age with newly diagsed multiple myeloma, had measurable disease, and had Cyclophosphamide, Bortezomib, Dexamethasone (CyBorD) Eastern Cooperative Oncology Group performance score, creatinine <309 4 l mol/l, absolute neutrophil count /l, and platelet count /l. All patients were mptomatic and needed therapy. All patients signed an formed consent. Sixty-three patients with newly diagnosed and symptomc myeloma were enrolled between 2006 and 2008 on a ase 2 trial of weekly oral cyclophosphamide 300 mg/m 2, bortezomib 1 3 mg/m 2 days 1, 4, 8, 11 (Cohort 1) or mg/m 2 days 1, 8, 15, 22 (Cohort 2) and dexamethasone high dose (Cohort 1) or high dose for 2 cycles, then low se for 2 cycles (Cohort 2) in a 28 day cycle. Patients eived prophylactic acyclovir and a quinolone antibiotic. sponse after 4 cycles was the primary goal. Secondary goals re progression-free survival (PFS), overall survival (OS), xicity of this combination and ability to harvest stem cells. tients were stratified to high risk or standard risk by Mayo ratification of Myeloma and Risk-Adapted Therapy SMART) criteria (Dispenzieri et al, 2007). It was assumed at most patients would proceed to SCT after stem cell llection and no maintenance after SCT was planned as part the trial. Survival was calculated using the Kaplan Meier method. was defined as time from registration to death from any treating physician. The median PFS was 40 0 months. The 5-year PFS and OS rates were 42% (95% confidence interval [CI]: 31 57) and 70% (95%CI: 59 82) for the entire group (Fig 1). Twenty-four of the 63 patients were considered high risk (38%) and had responses equal to standard risk patients (88% vs. 90%, P = 1 0) However, the median PFS was shorter in high risk patients at 27 6 months vs months in the standard risk patients. High-risk patients had a 5-year PFS of 33% (95%CI: 19 59) vs. 48% (95%CI: 33 69) in the standard risk group. Likewise a lower OS rate (54% (95%CI: N = ) vs. 81% (95%CI: 69 95)) (P = 0 04) was seen compared to standard risk patients (Fig 2). Fig 1. Kaplan Meier survival curves for all patients. OS, overall survival; PFS, progression-free survival. Reeder C. et al.; BJH, 2014

12 MCRN-001 Study Schema 1) Bortezomib-based induction 2) Bu-Mel ASCT 3) Len maintenance Reece D, et al, ASH 2015

13 What about RVD? Revlimid (lenalidomide), Velcade (bortezomib), Dexamethasone Thought to potentially be more potent but cost is an issue. To date phase III clinical trial data is lacking

14 Bortezomib, Lenalidomide and Dexamethasone (VRd) vs. Lenalidomide and Dexamethasone (Rd) in Previously Untreated Multiple Myeloma (SWOG S077): Design Patients without an intent for immediate ASCT Eight 21-day cycles of VRd Randomization N=525 Stratification: ISS (I, II, III) Intent to progression (yes/no) Bortezomib 1.3 mg/m 2 IV Days 1, 4, 8 & 11 Lenalidomide 25 mg/d PO Days 1-14 Dexamethasone 20 mg/d PO Days 1, 2, 4, 5, 8, 9, 11, 12 Six 28-day cycles of Rd Lenalidomide 25 mg/d PO Days 1-21 Dexamethasone 40 mg/d PO Days 1, 8, 15, 22 After induction Rd maintenance until PD, toxicity or withdrawal Lenalidomide 25 mg/d PO Days 1-21 Dexamethasone 40 mg/d PO Days 1, 8, 15, 22 Adapted from Durie B, et al: Presented at ASH 2015; Oral Presentation #25. All patients received aspirin 325 mg/d VRd patients received HSV prophylaxis 14

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16 Attal M. Presented at ASH 2015, Orlando Oral Abstract #391 Autologous Transplantation for Multiple Myeloma in the Era of New Drugs: A Phase III Study of the Intergroupe Francophone Du Myelome (IFM/DFCI 2009 Trial) Dr. Attal declined permission to report on his data presented at ASH Conclusions drawn by the ambassadors are presented here. 16

17 Autologous Transplantation for Multiple Myeloma in the Era of New Drugs: Study Design Registration: newly diagnosed patients with multiple myeloma RVD 1 Lenalidomide + Bortezomib + Dexamethasone 25 mg/day (Days 1 to 14) 1.3 mg/m 2 (Day 1, 4, 8, 11) 20 mg/day (Days 1,2,4,5,8,9,11,12) Randomization (stratified on ISS and FISH): n=700 well-matched patients Arm A (n=350) RVD 2 and 3 PBSC Collection (cyclophosphamide 3 mg/m 2 and G-CSF RVD 4 to 8 Lenalidomide maintenance 12 months (10 to 15 mg/day) Arm B (n=350) RVD 2 and 3 PBSC Collection (cyclophosphamide 3 mg/m 2 and G-CSF ASCT HDM 200 mg/m 2 RVD 4 and 5 Lenalidomide maintenance 12 months (10 to 15 mg/day) ISS: International Staging System; FISH: fluoresence in situ hybridization; PBSC: peripheral blood stem cell; G-CSF: granulocyte colony stimulating factor; ASCT: autologous stem-cell transplant; HDM: high-dose melphalan Adapted from: Attal M, et al. Presented at ASH 2015; Oral Abstract #

18 RVD +/- ASCT (IFM/DFCI 2009) Non-ASCT (%) ASCT (%) P-value ORR VGPR CR < yr PFS < Transplant is still required!!!! Attal et al, ASH 2015

19 RVD as the new standard? Fact 1: RVD > RD Fact 2: RVD + ASCT > RVD alone Fact 3: VTD > CyBorD Consider: Thalidomide not much cheaper than len, is rarely used in Canada and is more toxic Triplets are better than doublets Phase III data is evolving Barriers: Lack of front line indication for lenalidomide in transplant eligible patients $$$COST$$$ For each patient RVD costs about $14,000/cycle RVDx5 ($70K) then Len maint ($56K) =$126K/yr RVD x 12 = $168K/yr

20 The Canadian standard Transplant Eligible Patients CVD x 4-6 ASCT Mel200 Consolidation? Lenalidomide Maintenance Treatment of Relapsed disease Transplant Ineligible Patients CVD/VM P x 9 Bortez-based Maintenance/ continuous Tx Treatment of Relapsed disease

21 VMP vs MP CR = 33% vs 4% Median OS = 56.4m vs 43.1m Median TTNT = 30.7m vs 20.5m Established the NA/Alkylator/Steroid approach San Miguel et al, NEJM 2008

22 Alberta Multiple Myeloma Guidelines (Updated Feb, 2015)

23 the standard regime for hods CyBorD in transplant ineligible patients However, the presence of high-risk cytogenetics by FISH for all transplant ineligible tients diagnosed up until nsure a minimum of 12 is for surviving patients. nsplant at relapse were In the forty-five patients where results were available 11 (24%) had high-risk cytogenetics by FISH. There was no significant difference in achieving VGPR based on the presence or absence of high-risk disease (45% vs 44% respectively, p = 0.9). conferred a worse median PFS compared to those with no abnormality (8.2m vs 22.8m respectively, p = 0.02). Likely due to short follow-up no significant difference was seen with respect to median OS (29m vs not yet reached respectively, p = 0.39). as: bortezomib 1.5 mg/m 2 (as of August, 2013 we ib was also given on day days 1, 8, 15 and 22 and 15 and 22 with an aim to ent. The regimen could be at the discretion of the ity and response. achieved during frontline r CR (ncr), defined as but no confirmation by ical lab does not routinely free survival (PFS) and py was calculated by the ts were examined based l analysis was done on an Table 2. Best Response Achieved Response n = 78 (%) ncr 18 (23) VGPR 19 (24) PR 27 (35) SD 12 (15) PD 2 (3) p < p < Median PFS = 15.4m Median OS = 44.3m 8++(%)+ Figure 1: Progression free and overall survival of transplant ineligible patients treated in with CyBorD in the frontline setting based on depth of response. Compared with those who only achieved a PR or less (dashed line) to front-line treatment those who achieved ³VGPR (solid line) had an improved PFS (A) and OS (B). Conclusions Venner et al, IMWG 2015

24 Benboubker et al, NEJM 2014

25 Benboubker et al, NEJM 2014

26 FIRST: Updated OS Facon, ASCO 2015 Updated 4-year survival: 60% with Rd continuous vs 57% with Rd18 and 51% with MPT HR, hazard ratio; MPT, melphalan-prednisone-thalidomide; OS, overall survival; Rd, lenalidomide + low-dose dexamethasone until disease progression; Rd18, lenalidomide plus low-dose dexamethasone for 18 cycles. 1. Benboubker L, et al. N Engl J Med. 2014;371: Facon T, et al. FIRST Study: Updated Overall Survival in Stem Cell Transplant-ineligible Newly Diagnosed Multiple Myeloma Patients Treated With Continuous Lenalidomide Plus Low-dose Dexamethasone vs Melphalan, Prednisone, and Thalidomide. ASCO 2015, abstract #8524.

27 FIRST: Updated PFS Facon, ASCO 2015 A > 2-fold increase in 4-year PFS was observed with Rd continuous (33%) vs Rd18 (14%) and MPT (13%) a IRAC assessed; b Investigator assessed. HR, hazard ratio; IRAC, independent response adjudication committee; MPT, melphalan-prednisone-thalidomide; PFS, progression-free survival; Rd, lenalidomide + low-dose dexamethasone until disease progression; Rd18, lenalidomide plus low-dose dexamethasone for 18 cycles. 1. Benboubker L, et al. N Engl J Med. 2014;371: Facon T, et al. FIRST Study: Updated Overall Survival in Stem Cell Transplant-ineligible Newly Diagnosed Multiple Myeloma Patients Treated With Continuous Lenalidomide Plus Low-dose Dexamethasone vs Melphalan, Prednisone, and Thalidomide. ASCO 2015, abstract #8524.

28 Final pcodr recommendation December 2015 PCPA pricing agreement FINALIZED, now funded in AB and SK

29 Alberta Multiple Myeloma Guidelines (Updated Feb, 2015)

30 Questions Remain What about novel triplet regimens in the elderly? RVD vs RD (SO77 study and non-asct arm of IFM/DFCI 2009) Median PFS ~3-4yr Median OS = NR vs 63m (S077) Ixazomib/Lenalidomide/Dex vs Len/Dex Elotuzumab/Lenalidomide/Dex vs Len/Dex Daratumumab/Lenalidomide/Dex vs Len/Dex Durvalumab/Len/Dex

31 Questions Remain Is CyBorD still adequate? Is Maintenance worth the investment? What is coming?

32 Brief word on MRD We are entering an era where CR is becoming a more common event (>50%) Further refinement needed to assess burden of disease when this endpoint achieved Enter the new response endpoint of MINIMAL RESIDUAL DISEASE or MRD Options: Flow cytometry (FCM) Next Generation Sequencing (NGS)

33 Amount Monoclonal antibody Normal antibodies Size and shape Plasma Cell

34 Schematic representation to illustrate the paradigm of the deeper the response, the longer the (progression-free) survival (filled lines). Bruno Paiva et al. Blood 2015;125: by American Society of Hematology

35 MRD by flow cytometry Outcomes by MRD in MRC Myeloma IX Rawstron et al, JCO 2013

36 MRD by NGS Martinez-Lopez et al, Blood 2014

37 Avet-Loiseau H, et al. Presented at ASH 2015, Orlando Oral Presentation #191 Evaluation of Minimal Residual Disease (MRD) By Next Generation Sequencing (NGS) Is Highly Predictive of Progression Free Survival in the IFM/DFCI 2009 Trial Permission to include overview of key data presented at ASH 2015 provided by Dr. Avet-Loiseau. As reported by Dr. Peter Anglin 37

38 Evaluation of Minimal Residual Disease (MRD) in MM By Next Generation Sequencing: Categories of MRD: Note 3 categories Method Category Threshold of malignant cells Number of patients* Premaintenance Postmaintenance Flow cytometry Nextgeneration sequencing MRD negative < (68%) 232 (75%) MRD positive MRD negative < (36%) 86 (48%) MRD low-positive 10-6 to MRD positive *Note that the denominator is different for pre- and post-maintenance analyses. Adapted from: Avet-Loiseau H, et al. Presented at ASH 2015; Oral Presentation #

39 Patients without progression (%) Patients without Progression (%) Progression-free Survival by MRD Status at Pre vs. Post Maintenance by NGS ALL patients MRD at Pre-maintenance N at risk (events) MRD ng (<10) MRD positive (0) (0) p-value: p< Disease Negative (<10-6) Months since Randomization (0) (12) (2) (15) (2) (11) (6) (22) (4) (11) Positive (3) (17) (9) (6) MRD at Post-maintenance Disease Negative (<10-6) Using the <10-6 threshold at pre-maintenance, 3-year PFS was 83% for MRD-negative and 53% for MRD positive (p<0.0001). For post-maintenance, 3-year PFS was 90% for MRD-negative and 59% for MRD positive (p<0.0001) N at risk (events) MRD ng (<10) MRD positive (0) (0) p-value (trend): p< Months since Randomization (0) (0) (0) (0) (0) (6) (5) (9) Positive (3) (6) (5) (4) 36 4 (0) (1) Adapted from: Avet-Loiseau H, et al. Presented at ASH 2015; Oral Presentation #

40 Zimmerman TM, et al. Presented at ASCO 2015, Chicago. Oral abstract #8510. Phase II MMRC trial of extended treatment with carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (DEX) plus autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (NDMM) As reported by Dr. Martin Gyger 40

41 Response (%) KRd + ASCT in Newly Diagnosed RRMM: Evaluation of Minimal Residual Disease scr MRD negative ASCT n=37 n=21* Consolidation n=24 n=17* End of KRd n=8 n=8* *MRD by 10-color flow cytometry from indicated number of patients available for MRD evaluation. RRMM: relapsed or refractory multiple myeloma; ASCT: autologous stem-cell transplant; KRd: carfilzomib, lenalidomide and dexamethasone; scr: stringent complete response; MRD: minimal residual disease Adapted from Zimmerman TM, et al. Presented at ASCO 2015; Oral abstract #

42 Lancet Oncol, 2016, 17(8) e328-46

43 RELAPSED MM

44 Relapsed MM Using conventional therapy MM is incurable Relapse is inevitable! At relapse the disease remains incurable thus the goal of therapy is to regain and then maintain clonal control Rationale behind continuous therapy

45 Relapsed MM We are spoilt for choice! Approved and funded in the relapsed setting: Lenalidomide Bortezomib Pomalidomide Second ASCT Alkylator-steroid doublet as backbone Under consideration: Carfilzomib Ixazomib Elotuzumab Daratumumab Panobinostat

46 Approach Based on approvals by Health Canada we currently have two RRMM categories: 1. Double exposed and refractory prior lines

47 Who are we treating? Transplant Eligible Patients CVD x 4-6 ASCT Mel200 Consolidation? Lenalidomide Maintenance Treatment of Relapsed disease Transplant Ineligible Patients CVD/VM P x 9 Bortez-based Maintenance/ continuous Tx Treatment of Relapsed disease Transplant Ineligible Patients IMID-based induction: - Len/Dex (fixed vs continuous) - MPT - Len/Dex/Elotuzumab - Len/Dex/Ixazomib - Len/Dex/Dara TRIALS!!

48 Who are we treating? Beyond 2 nd line: Most patients double exposed Many (most?) are Len refractory Outcomes expected to be poor N = 422 Median OS (m) Median PFS (m) Line of therapy Non- ASCT ASCT p - value Non-ASCT ASCT p - value < < Exposure status DE DE DR Venner et al ASH 2015

49 Options (1-3 lines) 2 nd line: Lenalidomide based approach (85% or more)** MM-009/010 (Phase III, Len/Dex vs Dex) TTP = 13.4m OS = 38m ORR = 60.6% (CR = 15%) Bortezomib based approach: APEX (Phase III, Vel/Dex vs Dex) TTP = 6.2m OS = 29.8 ORR = 34% (CR = 9%) If it is allowed/funded If first response was durable **Venner, unpublished AB data

50 Options (double exposed) Pomalidomide is generally the funded Standard for treatment 3 rd line and beyond in Canada MM-003 Phase III, Pom-LoDex vs HiDex Inclusion: Relapsed/refractory to last line Received adequate treatment with both bort and len

51 MM-003: PFS and OS (ITT) Median Follow-up: 15.4 mos 85 pts (56%) on the HiDEX arm received subsequent POM San Miguel J, et al. Patient Outcomes by Prior Therapies and Depth of Response: Analysis of MM-003, a Phase 3 Study Comparing Pomalidomide + Low-Dose Dexamethasone (POM + LoDEX) vs High-Dose Dexamethasone (HiDEX) in Relapsed/Refractory Multiple Myeloma (RRMM). Oral presentation at: American Society of Hematology. 2013; December 7-10; New Orleans, LA.

52 What would we like to do? Upgrade existing classes of drugs: Carfilzomib (Kyprolis TM = IV Proteosome inhibitor) Ixazomib (Ninlaro TM = Oral Proteosome inhibitor) Pomalidomide (Pomalyst TM = IMID) Monoclonal Antibodies: Elotuzumab (Empliciti TM = IV monoclonal antibody) Daratumumab (Darzalex TM = IV monoclonal antibody)

53 100% Current Phase III trials New NA regimens in relapse 90% 80% 70% 60% 50% 40% 30% 20% <PR PR VGPR ncr CR 10% 0% 1. Stewart AK, et al, NEJM Dimopoulos MA, et al, Lancet Oncol, Moreau P, et al, NEJM Dimopoulus, et al, NEJM Palumbo, et al, NEJM Lonial S, et al, NEJM San Miguel, JF, et al, Lancet Oncol, 2014

54 Daratumumab Mab to CD38, a protein highly expressed on MM cells Single agent activity in phase II led to approval by FDA Raje N and Longo DL, NEJM, 2015

55 Daratumumab alone (SIRIUS trial) ORR = 31% PR = 18% VGPR = 10% CR = 0% scr = 3% NOT RECOMMENDED by pcodr Median PFS = 3.7m Updated Median OS = 17.5m Lonial S, et al, Lancet, 2016

56 Daratumumab combinations

57 Proportion surviving without progression Progression-free Survival DVd vs Vd 1.0 Median: not reached 1-year PFS* % 0.6 DVd Median: 7.2 months 26.9% Vd No. at risk Vd DVd Months HR: 0.39 (95% CI, ); P< % reduction in the risk of disease progression or death for DVd vs Vd *KM estimate; HR, hazard ratio. 7

58 Progression-free Survival DRd vs Rd Proportion surviving without progression month PFS* 18-month PFS* 83% % DRd 60% % 0.4 Rd Median PFS: 18.4 months 0.2 No. at risk 0 HR: 0.37 (95% CI, ; P <0.0001) Months Rd DRd *KM estimate; HR, hazard ratio. 63% reduction in the risk of disease progression or death for DRd vs Rd 58

59 Current Phase III trials - the Big 5 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% DaraRD KRD DaraVD KD IRD <PR PR VGPR ncr CR

60 Daratumumab Pros: Con: Novel mechanism of action Works well in combination with other drugs Infusion reactions Long infusion times lead to logistical challenges Ixazomib Pros: First Oral protesome inhibitor!! Also plays well with others Cons: Unsure of its place in context of cheaper bortezomib and potent carfilzomib Carfilzomib Pros: Very potent Useful as single agent and in combination Flexible dosing Cons: IV administration Schedule is challenging May have more (different?) side-effects

61 How will we be able to do it? Victim of our own success in that patients can live a long time ON therapy Median OS for ASCT-eligible patients with NA induction in AB is ~7.5 years without the benefit of the new NA s coming to the clinic Triplets of active NAs are fast evolving as the standard of care Novel Agent-based combination therapy is fast becoming the established standard with superiority over the widely used Canadian approach of NA/alkylator/steroid Triplet therapy in front line as Standard?? VTD RVD Triplet therapy at relapse as Standard?? KRD IRD DaraRD DaraVD EloRD PanoVD

62 How will we be able to do it? Novel treatment approaches have grade 4 financial toxicity Most combinations come with ~$100K/year price tag Indication for use of drug reflects how agent was used in trial setting No longer a question of single agent use More rigid criteria for routine use may limit a physicians creativity For longterm success we must have options!!

63 Canadian Multiple Myeloma Database (CMM-DB) A Proposal For Multi-Institutional Sharing of Clinical Data for Research Chris Venner, MD 2, Esther Masih-Khan, PhD 1, Tran Truong 7, Nizar Bahlis, MD 3, Anthony Reiman, MD 4, Michael Sebag, MD 5, Aldo Del Col 6, Donna Reece, MD 1 The goals of the Canadian Multiple Myeloma Database project are to: Evaluate the outcomes of multiple myeloma patients in Canada Identify the strengths and challenges in the management of Canadian multiple myeloma patients Understand the different regional needs to provide adequate care to multiple myeloma patients Understand the impact of novel therapeutic strategies on outcome of multiple myeloma patients Support the development of centers of excellence in multiple myeloma research

64 Thanks CCI Dr Andrew Belch Dr Linda Pilarski Dr Irwin Sandhu Dr Joanne Hewitt Dr Michael Chu Tatiana Nikitina TBCC Dr Nizar Bahlis Dr Paola Neri Dr Peter Duggan Dr Victor Zepeda Dr Jason Tay The patients, the hardest working members of the team! CCI Clinical Trials Unit Andrea Korcek Annette Yakimishyn Jennifer Gursky Joelle Roloff Trish Merrick CCI OPD Nurses Jennifer Ursela Jacie Lougheed Megan Armstrong Danielle Graham Shannon Ramos Cynthia Lau Alberta Cancer Foundation Celgene Johnson and Johnson Takeda MASS SAMPS Myeloma Canada