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

2. 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

3. 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

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

5. “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

6. Targeting mAbs

7. 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

8. 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

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

10. Immune Checkpoint Inhibitors

11. 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

12. 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

13. 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

14. d0 auto-SCT + d3 PBL reinfusion
LGS : Summary (overlay) by clinical site for MAGEA3 O/L Peptides
Event 1
Event
Event
Event
Event
Event
Event 18
days
d0 auto-SCT d3 PBL reinfusion
Days from auto-stem cell transplant
days
Cohen et al, ASH 2013

15. 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