Future Strategies for Myeloma Dr. John Quinn Beaumont Hospital

Background Survival continues to improve for myeloma patients Treatment: Continuous v Sequential Ageing population – Myeloma in the “hyperelderly” - >85yrs

Improved Response Rates in Myeloma The overall, more than VGPR and nCR/CR rates for a selection of phase 2 and phase 3 trials incorporating novel agents. A continuous improvement in response is seen with the combination of newer agents. A cautionary note is that many of these are small single-center experiences, and evidence that early responses translate into longer-term survival is not yet available. References for these trials are as follows: VAD,39 TD,31 RD,40 PAD,37 VTD,6 CVD,38 RVD,36 and CVRD.39 A. Keith Stewart et al. Blood 2009;114:5436-5443

Improving Outcomes ?Better versions of Velcade ?Better versions of Lenalidomide ?Maintenance Treatments New Era - Immunotherapy

NEJM, Jan 2015

Carfilzomib + Len/Dex v Len/Dex in RMM (ASPIRE Study) – NEJM 2015 792 patients 396 Carfilzomib + LD Median PFS 26.3 months P=0.0001 OS at 24 months 73.3% P=0.04 ORR 87.1% P<0.01 LD Median PFS 17.6 months OS at 24 months 65% ORR 66.7% Stewart et al, NEJM Jan 2015

ASPIRE Study Stewart et al, NEJM Jan 2015

Carfilzomib v Bortezomib (ENDEAVOR) Dimopoulos M, Lancet Oncology 2016

Carfilzomib v Bortezomib Chng et al, Leukemia 2017

Immunotherapy

Targets For Therapy in Myeloma From Ocio et al, Leukemia et al 2014 (IMWG)

Monoclonal Antibodies Mabs Ends in “mab” Best known: Rituximab - Lymphoma Daratumumab Isatuximab Elotuzumab

Monoclonal Antibodies in Early Phase Studies in Myeloma Drug Target Combined with N ORR Elotuzumab CS1 - LD BD 35 29 73 28 0% 82% 84% 40% Daratumumab CD38 32 42% nBT062-DM4 CD138 4% Lorvotuzumab CD56 37 44 7% 56% Dacetuzumab CD40 39% Lucatuzumab Tabalumab BAFF 48 46% Silituximab IL-6 D 49 21 19% 57% IPH2101 KIR L 13 31%

Monoclonal Antibodies Older chemotherapy drugs target DNA Mabs – target something on the myeloma cell surface

Monoclonal Antibodies Need a target Ideal target – something on myeloma cells – but not on many other cells! Daratumumab – CD38 Isatuximab – CD38 Elotuzumab – CS1/SLAMF7

Mabs in Myeloma From Van de Donk et al, Blood 2016

Daratumumab

Daratumumab

Daratumumab Dimopoulos et al, NEJM 2016

Elotuzumab

Elotuzumab Lonial et al, NEJM 2015

Elotuzumab works via a dual mechanism of action by both directly activating Natural Killer Cells and through antibody-dependent cell-mediated cytotoxicity (ADCC) to cause targeted Myeloma cell death Elotuzumab Elotuzumab

Elotuzumab Synergizes with Lenalidomide to Enhance Myeloma Cell Death Induces myeloma cell injury and lowers threshold for NK cell-mediated killing of myeloma cells by elotuzumab Direct NK Cell aactivation NK Cell Elotuzumab SLAMF7 ADCC CD16a + Myeloma Cell Lenalidomide Enhances adaptive and innate immune system including production of IL2 to increase NK cell activity Balasa et al (Cancer Imm and Immunotherapeutics), 2015

Mabs – Side-Effects Main issue is “infusion-related” symptoms Typically a mild/moderate allergic type reaction Chills, fever, rash – rarely severe Treated with paracetamol, steroid, antihistamine Reduce rate of infusion or stop temporarily

Checkpoint Inhibitors PD1 Blockade Nivolumab and Pembrolizumab Highly active in melanoma, lung cancer, and Hodgkin lymphoma (now reimbursed in Ireland via NCCP)

PD1-Inhibitors

PD1 Inhibitors Side-Effects related to immune “activation” Colitis Pneumonitis Thyroiditis Myocarditis Managed with steroids

Targeting BCMA MaBs CAR-T cells Sherbenou et el, Clinical Lymphoma Myeloma and Leukemia 2017

BCMA GSK2857916 Anti-BCMA MaB + MMAF (chemo agent) First experience reported at ASH 2016 Clinical Trials in patients with relapsed/refractory disease Hopefully – BCNI trial in mid 2018

CAR-T Cells JAMA Patient Page

CAR-T Cells

CAR-T Cells Chimeric Antigen Receptor (CAR) Engineer a receptor that targets an antigen on cancer cell surface Take patient T-cells In lab –T-cells are modified to express the CAR Expanded Re-infused to target the cancer cells Major side-effects: Cytokine Release Syndrome and Nerve Toxicity Approved in US for childhood ALL and DLBCL

CAR-T Cells in Myeloma ASCO 2017 Fan et al 19 patients with relapsed refractory disease 100% response rate 95% complete response Median F/up – 6 months CRS - 74% - mild in most cases 2nd study presented at ASCO showed very similar findings

Future of Myeloma Cure vs Control Can myeloma be cured with current treatment? Possibly/Probably in a subgroup of patients

Curable Blood Cancers Chronic Myeloid Leukaemia t(9;22) Glivec Acute Myeloid Leukaemia Allogeneic Bone Marrow Transplant Younger patients Hodgkin Lymphoma Unique Disease Rare tumours cells in inflammatory microenvironment Young patients

Lessons From Curable Blood Cancers Early deep responses – generally a good thing Allogeneic transplant is not the answer (may be considered in highly selected cases) Learn how to reduce longterm toxicity – 2nd cancers

Autologous Transplant Here to stay for now Backbone of treatment for those <65-70 Most recently published evidence favours lenalidomide maintenance over no maintenance ?Other drugs ?How long

Anti-Myeloma Drugs Dexamethasone Prednisolone Melphalan Cyclophosphamide Bendamustine Thalidomide Lenalidomide Pomalidomide Bortezomib Carfilzomib Ixazomib Marizomib Opromazib Daratumumab Isatuximab Elotuzumab Panobinostat

Future of Myeloma 3 drugs better than 2 drugs Is 4 better than 3 Balance toxicity against efficacy Caution as we add in Mabs/Others to frontline therapy NB: Clinical Trials – The standard of care

Future Myeloma Treatment Younger (<65-70) At Diagnosis Dara + Dex + Velcade/Other + Cyclophosphamide/Lenalidomide Stem Cell Transplant Maintenance Relapse Anti-BCMA MaB Anti-BCMA CAR-T cells Pomalidomide

Future Myeloma Treatment Older >70 Velcade + Dex or Len + Dex Plus another drug - ?Melphalan ?Daratumumab CAR-T cells? Other MaBs? Tolerability in older patients is a major factor >85 yrs Increasing numbers Special group Other illnesses QOL Practical issues

Summary Outcomes continue to improve Several exciting new drugs in development and clinical trials How best to “package” treatments is a big challenge