Immunotherapy for Multiple Myeloma Hearn Jay Cho MD, PhD Mt. Sinai School of Medicine

Disclosures Clinical research support Laboratory research support Ludwig Institute for Cancer Research Laboratory research support Cancer Research Institute NIH/NCI I will discuss investigational applications of FDA-approved and investigational agents

Rationale for Immunotherapy Durable complete remissions reported for allogeneic stem cell transplantation Immunologic therapy, “graft-versus-tumor effect” Donor lymphocyte infusion rescues patients who relapse after allo-transplant T cell-mediated anti-tumor immunity Humoral and cellular immune responses against myeloma-associated antigens detected in patients Pre- and post-treatment, allo transplant

Immunotherapeutic Strategies “Targeting” monoclonal antibodies (mAbs) Immune checkpoint inhibitors Adoptive cell therapies Transgenic T cell receptor (TCR) Chimeric antigen receptors (CAR) Therapeutic tumor vaccines

“Targeting” mAbs Monoclonal antibody Antigenic target Elotuzumab SLAMF7 (CS-1) Daratumumab SAR650984 CD38 Siltuximab IL-6 Tocilizumab IL-6R Dacetuzumab CD40 MA5 MUC-1 BT-062* CD138 IPH-2101† KIR * Immunotoxin conjugate

Targeting mAbs

Targeting mAbs Elotuzumab Daratumumab Elo Len Dex Ph 2 relapse, PFS 33 months, ASCO 2013 FDA Breakthrough Therapy 2014 Daratumumab Dara ± Len Dex Ph1/2 relapse, high response rate, ASH 2013 FDA Breakthrough Therapy/ Fast Track 2014

Targeting mAbs Mechanisms Elotuzumab Activates NK cells, renders them capable of killing SLAMF7(-) tumor cells. Cancer Immunol Immunother 62:1831 Daratumumab CD38 ectoenzyme catalyzes critical step in NADAdenosine metabolism, modulates TCR signaling. J Mol Med 91:165

Immune Checkpoint Inhibitors Antibody Target Ipilimumab* Tremelimumab CTLA-4 Pembrolizumab* Nivolumab Pidilizumab PD-1 MPDL3280A** MEDI4736 PD-L1 * FDA approved ** Breakthrough Therapy

Immune Checkpoint Inhibitors

Checkpoint Inhibitors Trials Basket trials Ipilimumab + Nivolumab heme malignancy MPDL3280A in solid tumors and heme malignancy Combination Pembrolizumab + len/dex Pidilizumab + DC fusion vaccine Post-allo-SCT Ipilimumab

Vaccine Immunotherapy Cell-based vaccines Dendritic cell vaccines Tumor cell vaccines Autologous or cell lines MHC-restricted peptide vaccines “Universal” vaccines Recombinant proteins Synthetic long peptides Plasmid DNA vaccines

Myeloma-associated Antigens Idiotype Myeloma-specific Poor results in clinical trials Tumor-associated Antigens WT1 Muc1 hTERT Cancer-Testis Antigens Expressed in many cancers Restricted expression in normal tissue Type I MAGE (MAGE-A3 and CT7), NY-ESO-1, SSX2 expressed in myeloma

d0 auto-SCT + d3 PBL reinfusion LGS2009-005: Summary (overlay) by clinical site for MAGEA3 O/L Peptides Event 1 Event 2 4 Event 8 9 10 Event 11 12 Event 13 14 Event 15 16 Event 18 days d0 auto-SCT + d3 PBL reinfusion Days from auto-stem cell transplant days Cohen et al, ASH 2013

Future Directions Combination immuno- and targeted therapy Cytotoxic + immuno/ Auto-SCT + immuno ImiDs + immunotherapy Polyvalent vaccines Consolidation for non-auto-SCT candidates MGUS/ smoldering MM