1. Future Strategies for Myeloma
Dr. John Quinn
Beaumont Hospital

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

3. 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:

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

5. NEJM, Jan 2015

6. 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

7. ASPIRE Study
Stewart et al, NEJM Jan 2015

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

9. Carfilzomib v Bortezomib
Chng et al, Leukemia 2017

10. Immunotherapy

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

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

13. 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%

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

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

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

17. Daratumumab

18. Daratumumab

19. Daratumumab
Dimopoulos et al, NEJM 2016

20. Elotuzumab

21. Elotuzumab
Lonial et al, NEJM 2015

22. 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

23. 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

24. 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

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

26. PD1-Inhibitors

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

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

29. 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

30. CAR-T Cells
JAMA Patient Page

31. CAR-T Cells

32. 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

33. 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

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

35. 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

36. 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

37. 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

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

39. 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

40. 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

41. 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

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