Multiple Myeloma in 2016 Progress and Challenges DONNA E. REECE, M.D. PRINCESS MARGARET CANCER CENTRE 01 APRIL 2016

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1 Multiple Myeloma in 2016 Progress and Challenges DONNA E. REECE, M.D. PRINCESS MARGARET CANCER CENTRE 01 APRIL 2016

2 Key Features of Myeloma Biology Myeloma is not one disease 1 At least 7 subtypes based on cytogenetic and molecular features Highest risk cytogenetic subtypes by FISH» t(4;14)» del 17p» t(14;16)» abnormalities of chromosome 1 Clonal heterogeneity and clonal tiding clones present at diagnosis Different clones can dominate, driven by therapy or other pressures This dynamic has therapeutic implications t(4;14) del17p Loss of 17p 1 Bergsagel L, Chesi M. Int J Hematol 2013; 97: ; 2 Keats JJ, et al. Blood. 2012;120:

3 Key Features of Myeloma Biology Pathophysiology depends on direct interaction with marrow microenvironment 1 -- Direct adhesion of myeloma/stromal cells -- Cytokines release (IL-6, IGF-1, etc) -- Activation of key signaling pathways - PI3K - JAK/STAT - NF-kB 1 Manier et al. J Biomed Biotechnol. Epub 2012 Oct..

4 Multiple Myeloma in 2016: Challenges How do we individualize therapy in this heterogenous disease? Clinical trials lump all subtypes together Biomarker-driven therapy has lagged behind that utilized in solid tumours How do we best use the newer techniques that measure residual disease? Are they prognostic factors or determinants of therapy? How do we sequence the new drugs and drug combinations? We have multiple regimens with good anti-tumor efficacy, but we need to define the best strategies to optimize them The promise of immunotherapeutic approaches Which are the most effective in myeloma and for what subtypes? When it the best time point to use them? Reliable cure remains elusive

5 Prognostic Scores for Newly Diagnosed Patients Derived from phase 3 trials comparing bortezomib-based induction therapy with either VAD or thalidomide + dex before ASCT 1 N= 2197 patients Risk of early death related to: ISS 3 (p=0.020) t(4;14) and/or del 17p (p=0.0004) High LDH (p=0.012) 1 Moreau P, et al. J Clin Oncol June : Epub ahead of print.

6 Canadian Algorithm for Myeloma Therapy Funding is evidenced-based years and fit > years and/or frail ASCT +/- maintenance Chemotherapy Progression Second ASCT if months from first Second-line therapy (Lenalidomide- or bortezomib-based; carfilzomib approved) Third-line therapy (Bortezomib- or IMiD-based; clinical trial) Double refractory * (Pomalidomide + dex, daratumumab [compassionate]; clinical trial or re-use previous drugs) Palliation/Death *To lenalidomide and bortezomib

7 Algorithms for Myeloma Therapy in USA Age, Co-morbidities years and fit ASCT +/- maintenance 2 or 3-drug combo (Len + dex; RVD; CyBorD)? Patient/MD choice > years and/or frail Chemotherapy Progression Early relapse Lenalidomide + dex +/- elotuzumab, ixazomib or carfilzomib; Bortezomib + dex +/- other agent; pomalidomide + dex +/- other drug Advanced relapse (Pomalidomide + dex +/- other, daratumumab, carfilzomib, bendamustine, clinical trial or re-use previous drugs) Palliation/Death

8 Current Methods to Measure Therapeutic Response Serum and/or urine electrophoresis and immunofixation IFE requires immunologist to interpret visually M-protein may be absent at the time of disease progression SPEP (light chain escape; non-secretory relapse) Serum free light chain (FLC) assay Measures both monoclonal and polyclonal light chains Considerable variability in results Not recognized as endpoint by FDA Skeletal survey 30-50% of bone mass must be destroyed before conventional xrays can detect damage Only rarely shows improvement in osteolysis Serum Freelite assay Conventional radiographs Antibody target

9 Newer Methods to Measure Therapeutic Response Bone marrow MRD (multi-parameter flow cytometry, deep sequencing) 1 Flow Cytometry Fresh sample (<24-48 hours) NGS (Sequenta) Frozen sample Feasible in 100% Feasible in 92% (somatic hypermutation) Sensitivity Sensitivity 10-6 Does not require diagnostic sample Worldwide common protocol underway Needs diagnostic sample to identify clone Fully standardized Other methods Circulating tumor DNA Imaging (PET-CT, MRI) 1 Adopted from Avet-Loiseau H, et al. Blood 2015; 126: abstract 191.

10 Bone Marrow MRD: Prognostic Factor or Determinant of Therapy? Patients achieving MRD-negativity have better PFS and overall survival IFM/DFCI 2009 Study 4 MRD at post-maintenance ASCT patients 1,2,4 Non-transplant eligible patients 3 Should patients achieving MRDnegativity discontinue therapy? Long-term maintenance therapy with lenalidomide after ASCT associated with risk of second primary malignancies Patients without progression (%) N at risk (events) MRD neg (<10-6 ) MRD positive 0 6 P-value : p< Negative (<10-6) Positive 80 (0) 80 (0) 80 (0) 80 (0) 80 (3) 73 (3) 57 (5) 33 (0) 9 51 (0) 51 (0) 51 (0) 51 (3) 47 (9) 36 (5) 26 (9) 6 (0) 3 30 Months since randomization Paiva B et al; Blood. 2008, 112: ; 2 Rawstron AC, et al. J Clin Oncol 2013; 31: ; 3 Martinez-Lopez, J, et al. Blood 2014; 123: ; 4 Avet-Loiseau H, et al. Blood 2015; 126: abstract 191.

11 Cell-free DNA dissolved in blood is derived from many normal cells and a few tumor cells Source of cfdna Luis A. Diaz Jr, and Alberto Bardelli JCO 2014;32:

12 Summary of Somatic Mutations in KRAS, NRAS, BRAF, PIK3CA or EGFR Detected in Cell-Free DNA Isolated from Plasma of 33 MM Patients 70% 60% 50% 40% 20/33 19/33 30% 11/33 20% 7/33 10% 0% Mutation in any gene Mutation in KRAS, NRAS, or BRAF KRAS mutation NRAS mutation 3/33 3/33 BRAF mutation PIK3CA mutation 2/33 EGFR mutation This method can also detect structural alterations and immunoglobulin gene translocations Trudel S, Pugh T, unpublished observations.

13 Imaging in Myeloma Better Techniques Are Needed and Are Under Study Assessment of the extent of myeloma skeletal involvement has been suboptimal Traditional skeletal survey has many limitations PET scan good for focal lesions and extramedullary disease but less sensitive for diffuse involvement of spine MRI useful for spinal cord and nerve root involvement PET/CT was evaluated in large trial of modern therapy (RVD induction ASCT RVD consolidation len maintenance) Negativity is prognostic for better PFS and OS PET/CT results are complementary to MRD status Still lack measure of proliferative capacity of myeloma cells PFS by PET-CT Status before Maintenance in ASCT Patients 1 Positive Negative 1 Moreau P et al. Blood 126: abstract 395.

14 ASCT versus Chemotherapy as First-line Therapy Recent Results Recent phase 3 studies confirm a significant PFS advantage, 1-3 and in one study, a overall survival advantage, 2 of ASCT over chemotherapy for first-line therapy Italian RV-MM-209 study (Palumbo et al. 1 ) Italian study (Gay et al. 2 ) DFCI/IFM 2009 study (Attal et al. 3 ) DFCI/IFM 2009 Study results 3 RVD 5 RVD MEL200 + ASCT 2 RVD DFCI/IFM 2009 Study: PFS Lenalidomide maintenance x 12 mos. 1 Palumbo A, et al. N Eng J Med 2014; 371: ; 2 Gay F, et al. Lancet Oncol 2015; 16: ; 3 Attal M, et al. Blood 2015; 126: abstract 391.

15 Best Results from Phase 3 Trials of ASCT as Part of First-line Therapy Harousseau 1 Cavo 2 Induction Rx Bortezomib + Dex VTD ASCT + Maintenance 1 or 2 (lenalidomide maintenance in some) 2 + VTD consolidation x 2 + dex maintenance Sonneveld 3 PAD 1 or 2 + bortezomib maintenance x 2 years Rosinol 4 Attal 5 VTD RVD 1 + VT = bortezomib and thalidomide maintenance x 3 years 1 + RVD x 2 + lenalidomide maintenance x 1 year VGPR (CR+nCR) (%) PFS (Median) 68% (39%) 36 mo 89% (71%) NYR 68% (3-year) 76% (49%) 35 mos NA (46%) 56.2 mos --(58%) 34 mos OS (Median) NYR 81% (3-year) NYR 86% (3-year) NYR 61% (5-year) NYR 74% (4-year) NYR 88% (3-year) 1 Harousseau JL, et al, J Clin Oncol 2012;28: ; 2 Cavo M.et al. Lancet 2010;376: ; 4 Sonneveld P, et al.j Clin Oncol 2012;30: ; 4 Rosinol L, et al. Blood 2012;120: ; Attal M, et al. Blood 2015; 126: abstract 391.

16 KRD Induction and Consolidation Potential Progress in First-line Therapy Zimmerman TM, et al. ASCO 2015: abstract 8510.

17 KRD: Response Rates Over the Course of Treatment Zimmerman TM, et al. ASCO 2015: abstract 8510.

18 Post-ASCT Therapy: CTN Trial VRD x 3 SC collection CY + G-CSF Melphalan 200 mg/m 2 + ASCT Melphalan 200 mg/m 2 + ASCT Melphalan 200 mg/m 2 + ASCT Melphalan 200 mg/m 2 + ASCT VRD consolidation Len maintenance

19 First Line Therapy in Transplant-ineligible Patients: Summary of Phase 3 Trial Results Moreau P, et al. Blood 2015; 125(20):

20 Algorithms for Myeloma Therapy in US Age, Co-morbidities years and fit ASCT +/- maintenance 2 or 3-drug combo (Len + dex; RVD; CyBorD)? Pt/MD choice > years and/or frail Chemotherapy Progression Early relapse Lenalidomide + dex +/- elotuzumab, ixazomib or carfilzomib; Bortezomib + dex +/- other agent; pomalidomide + dex +/- other drug Advanced relapse (Pomalidomide + dex +/- other, daratumumab, carfilzomib, bendamustine, clinical trial or re-use previous drugs) Palliation/Death

21 Phase 3 Trials with Lenalidomide + Dex +/- New Agent for Relapsed or Refractory Myeloma after 1-3 Prior Regimens ASPIRE 1 Len + dex vs Len + dex + carfilzomib ELOQUENT-2 2 Len + dex vs Len + dex + elotuzumab TOURMALINE-MM1 3 Len + dex vs Len + dex + ixazomib 1 Stewart AK, et al. N Engl J Med 2015; 372: ; 2 Lonial S, et al. N Engl J Med 2015; 373: ; 3 Moreau P, et al. Blood 2015; 126: abstract 727

22 Phase 3 Studies Comparing Len + Dex versus Len + Dex + New Agent in Patients with1-3 Prior Regimens Third Agent % with prior Len % with high-risk cytogenetics Response rates for triplet vs doublet (%) PFS for triplet vs doublet (mos) Interim OS for triplet vs doublet (mos) Carfilzomib vs13 87 vs vs 17.6 (p=0.0001) Elotuzumab vs vs vs 14.9 (p=0.014) Ixazomib vs vs vs 14.7 (p=0.012) 73% vs 65% (24 months) 43.7 vs 39.6 (p=0.026) -- 1 Stewart AK, et al. N Engl J Med 2015; 372: ; 2 Lonial S, et al. N Engl J Med 2015; 373: ; 3 Moreau P, et al. Blood 2015; 126: abstract 727.

23 Other Phase 3 Trials for Relapsed or Refractory Myeloma after 1-3 Prior Regimens Other trials with bortezomib as comparator ENDEAVOR 1 BTZ + dex vs carfilzomib vs dex PANORAMA-1 2 BTZ + dex vs BTZ + dex + panobinostat UPCOMING TRIAL RESULTS 3 Len + dex vs Len + dex + daratumumab 1 Dimopoulos MA, et al. Lancet Oncol. 2016;17: 27-38; 2 San Miguel SF, et al. Lancet Oncol. 2014;15:

24 How do we best treat early relapse now that these new regimens are available? Factors to consider in selection of regimen Did patient progress on lenalidomide maintenance or after prior len + dex? Other factors potential issues Risk group Comorbidities Renal function Distance from cancer centre Distance from cancer centre Is there a role for all 3 regimens in the same patient? Relapse Ixazomib Relapse Relapse After 1 prior regimen After 2 prior regimens After 3 prior regimens Elotuzumab Carfilzomib Lenalidomide + dex

25 Adding 3 rd Agent to a Failing Regimen What evidence do we have? Retrospective study of addition of biaxin to Len + dex at the time of progression 1 N = 23/33 evaluable after 2 months of biaxin PR in 43%, stable disease SD in 57% Median PFS 5.98 months Retrospective study of addition of cyclophosphamide (CY) to Len + dex at the time of progression 2 N = 54 pts given 1 month of therapy of weekly oral CY PR in 41%, stable disease in 44% Median PFS from addition of CY = 8 months Median PFS from start of Len + dex = 25 months Compares favorably with prospective trial of CPR triplet (CY + Len + prednisone) with PFS = 14.3 months 3 Would a similar strategy work using lenalidomide or pomalidomide and dex as a backbone and moving from carfilzomib to elotuzumab or ixazomib or vice versa? 1 Kaedbey R, et al. IMW 2015; abstract PO-375; 2 Alahmadi M, et al. ASH abstract 2015, submitted; 3 Reece D, et al. Br J Haematol 2015; 168: 168:

26 Immunotherapy in Myeloma Targets for mabs IL-6 Siltuximab CD38 CXCR4 CD56 CD40 SLAMF7 Indatuximab Milatuzumab Pembrolizumab Nivolumab Atezolizumab CD138 CD74 PD-1 β2m CD70 MM cell CD317 BCMA FDA Approved Elotuzumab Daratumumab In clinical development Preclinical activity Adapted from Lonial et al. Leukemia 2015;doi: /leu

27 New Drugs/Therapeutic Approaches: Immunotherapy with Monoclonal Antibodies in Relapsed/Refractory Myeloma First effective mabs in myeloma have been identified and approved by FDA Elotuzumab + Len + dex Single agent daratumumab approved by FDA Now, the race is on to define role of anti-pd1 or anti-pd1l-antibodies in myeloma Drug Name Target Median # prior regimens Elotuzumab 1 SLAMF7 2 Regimen ORR (%) Len + dex* (1-3 prior therapies) PFS (mos) Daratumumab 2 CD38 5 Single agent* Daratumumab 3 CD38 5 Len + dex 88 Too early SAR (Isatuximab) CD38 6 Single agent 24 NA Isatuximab 5 CD38 6 Len + dex BT062 6 CD138 3 Len + dex 78 Too early 1 Lonial S, et al. N Engl J Med. 2015;373:62; 2 Lonial S, et al. Lancet 2016 Jan 6 [Epub ahead of print]; 3 Lokhorst HM, et al. J Clin Oncol. 2013;31: abstract 8512; 4 Martin T, et al. J Clin Oncol 2014; 32(Suppl. 5): abstract 8532; 5 Martin TG, et al. Blood. 2014;124: abstract 83; 6 Kelly KR, et al. Blood. 2014;124: abstract *FDA approved

28 What s New in Myeloma Therapeutics? Oral proteasome inhibitors Monoclonal antibodies Kinase inhibitors HDACs Novel mechanisms Immunotherapies Ixazomib Elotuzumab Vermurafenib Panobinostat Venetoclax CAR-T Oprozomib Daratumumab Afuresertib Ricolinostat Selinexor BITE Isatuximab Dinaciclib PIM (LGH447) PDL-1/PD-1 inhibitors Trametinib = Princess Margaret Myeloma Program study HDAC, histone deacetylase. Adopted from Stewart AK. Building on Myeloma Therapy: Emerging Molecular Targets and Immunotherapeutic Approaches. Presented at MMRF ASH Satellite Symposium, 04 December 2015, Orlando, FL.

29 Summary and Conclusions Progress and Challenges in Multiple Myeloma New risk stratification has been described However, current systems still miss a significant proportion of patients with more aggressive disease New methods to assess residual myeloma are now available MRD and imaging studies currently available These are mainly prognostic at this time Many new agents/combinations have been introduced Optimal sequencing of new regimens is not known Effective mabs are finally available Need to focus on strategies not just regimens An important goal is to personalize therapy This will likely require even more effective prognostic systems, subtype identification, targeted agents and biomarkers of response