1. Toxicities and clinical issues with Immunotherapies
Reuben Benjamin
King’s College Hospital

2. Overview of emerging Immunotherapies for Myeloma
Monoclonal antibodies
Checkpoint inhibitors
Bispecific T-cell engagers (BiTEs)
CARs, TCR therapy
Next generation ImiDs (CelMods)
Vaccines
Allogeneic SCT

3. Toxicity profile for immunotherapies
Distinct toxicity profile compared with chemotherapy
Mediated by immune activation
Skin : pruritis, rash
Gut : colitis
Liver : autoimmune hepatitis
Endocrine : hypothyroidism
Also immune mediated neuropathy, myositis, arthritis, pneumonitis
Treatment generally with steroids

4. Toxicity of checkpoint inhibitors in myeloma
Keynote 183 Trial
- Pomalidomide/Dex +/- Pembrolizumab for relapsed MM ( >2 lines of therapy)
- Number of deaths = 29 (Pembro arm) v 21 (control arm) HR =1.61 at median of 8.1 months
- Grade 3-5 toxicity 83% v 65%
- SAEs 63% v 46%
- ORR 34% v 40%

5. Toxicity of checkpoint inhibitors in myeloma
Keynote 185 Trial
- Lenalidomide/Dex +/- Pembrolizumab for upfront treatment of SCT ineligbile MM
- Number of deaths = 19 (Pembro arm) v 9 (control arm)
HR = 2.06 at median of 6.6 months
- Grade 3-5 toxicity 72% v 50%
- SAEs 54% v 39%
- ORR 64% v 62%

6. Toxicity of checkpoint inhibitors in myeloma
Causes of death in Pembro arm (unrelated to progressive disease)
Myocarditis *
Stevens-Johnson syndrome *
myocardial infarction
pericardial hemorrhage
cardiac failure
respiratory tract infection
neutropenic sepsis
sepsis
multiple organ dysfunction
respiratory failure
intestinal ischemia *
cardio-respiratory arrest
Suicide
pulmonary embolism
cardiac arrest
pneumonia
sudden death
large intestine perforation *

7. Monoclonal antibodies in myeloma
anti-CD38
Daratumumab, Isatuximab, MOR202
anti-CS1
Elotuzumab
BiTEs
BCMA-CD3
CD138-CD3

8. Toxicity of monoclonal antibody therapy in myeloma
Infusion related reactions
10-71%
Haematological
20-28%
Interference with laboratory assays
M protein
Indirect antiglobulin test

9. Bispecific T cell engager antibodies (BiTEs)

10. BiTEs for myeloma CD3-BCMA antibody CD3-CD138 antibody Trials ongoing
? Expected toxicity similar to Blinatumomab in B-ALL
Infusion reactions
Cytokine release syndrome
Neurotoxicity
Infections

11. Adoptive T-cell therapy for myeloma
CAR T-cell therapy
TCR therapy
DLI post RIC Allogeneic SCT

12. Chimeric antigen T cell (CAR-T) therapy

13. CAR-T cell evolution

14. CAR-T cell manufacturing process
- Autologous CARs
- Allogeneic DLI CARs
- Off the shelf CARs

15. Variation in CAR-T cell products
Same antigen target but different scFvs
Different costimulatory domains
CD28, 41BB, 28+41bb
Different gene transfer techniques
Retroviral v lentiviral v non viral
Range of cell manufacturing processes
Autologous v Allogeneic (DLI-CAR) v off-the-shelf CARs

16. CAR-T cell therapy for myeloma
BCMA CAR
APRIL CAR
CS-1 CAR
CD19 CAR

17. Complications of CAR-T therapy
Cytokine release syndrome
Neurotoxicity
Infections
Cytopenia
GVHD (with allogeneic CARs)

18. Cytokine release syndrome
Occurs in 20-40% of CAR treated patients
Fever, malaise, tachycardia, hypotension, capillary leak, renal failure, DIC
Severity related to disease burden
Elevation of serum cytokines
Treatment
aggressive supportive care
IL-6R blockade (Tociluzumab)
Steroids

19. CRS management

20. Neurotoxicity Occurs in 30-40% of CAR treated patients
Confusion, delirium, aphasia, seizures, coma
Pathogenesis likely cytokine mediated
Treatment
Generally reversible
Supportive care including ventilation
Antiepileptics
Steroids

21. Cytopenia post CAR therapy
Secondary to lymphodepletion
HLH triggered by cytokine release syndrome
GVHD of marrow (with allogeneic CARs)

22. Immunotherapy for myeloma - challenges
Identify appropriate patient for a specific immunotherapy
Identify predictive biomarkers for efficacy and toxicity
Refine strategies for early recognition and management of expected and unexpected adverse events
Education and training of clinicians and other health professionals in complications of immunotherapy
Daycare/inpatient capacity

23. Immunotherapy for myeloma - recommendations
Use Immunotherapy with caution !
Always think of potential immune related side effects
Perform comprehensive investigations
Serum cytokines
Immune subsets analysis
Biopsy and IHC of affected organ
Appropriate imaging
Involve relevant specialists early
Low threshold for HDU/ICU care
Report/publish all adverse events
Share management strategies through regional/national disease groups