1. Medical overview of Myeloma
MMI Patient and Family awareness day 2018
Sligo park Hotel Nov 8

2. Nothing to disclose

3. Overview Disease Overview -Common presenting symptoms
- Diagnostic studies
Indications for treatment/How I approach initial treatment
Treatment considerations at relapse
Supportive care
So today Im going to try and give you all a brief overview of myeloma so that we are all pn the same page , and then Im going to focus a lot of time on how I approach the initial treatment of patients recently diagnosed with myeloma because I think that really is the space where we can really impact on peoples lives and give them really long periods of remission and then finally because we have so many new drugs in the last few years , Im going to talk about some of the treatment considerations when the disease returns

4. What is myeloma
Cancer of a type of white blood cell called plasma cells
Function of plasma cells is to make proteins called antibodies which help our bodies fight infections
Why does myeloma develop ? --- unknown
A range of different genetic mutations now identifiable in the myeloma cells of different patients
Multiple Myeloma is a cancer of a certain type of white blood cells . We all have several different types of white blood cells , their function is try and fight different types of infection
The particular type of white blood cells that are responsible for multiple myeloma are called plasma cells. The reason for developing myeloma is not known at this time . But the triggers that cause the plasma cells to develop into cancerous cells are probably different in different people and in particular the genetic abnormalities that we can now test for show that there are different genetic abnormalities in different patient . Importat point that ill come back to later

5. Patients with Myeloma are living much longer with a much better quality of life now compared to fifteen years ago
Survival of patients tripled in last fifteen years
Not Curable – relapsing , remitting course

6. 14th most common type of cancer 2nd most common type of blood cancer
Disease of adults and older people – most people are 60 yrs +
< 1% are less than under 35 years at diagnosis
More men than women affected
Increasing incidence
So myeloma I feel is quite a common disease in the field of blood cancers , second most common cancer we treat and there are increasing numbers living with myeloma all the time but nonetheless most often when you talk to patients who have been recently diagnosed , or their families , you realise a lot of people have never heard of it – need to raise awareness. One of the interesting features of the disease is that it’s a disease affecting adults , average age of patients when diagnosed is in their 60s , children don’t get it generally , there is a case report of a 14 year old and an 18 year old in the literature but in general less than 1% are < 35 . And we don’t know why this is.
Incidence increasing and seems to be more than simply due to the aging of the population

7. Symptoms Put in picturs
I want to talk a little bit about symptoms that patients report to us . To go back a bit first Myeloma as we said is a cancer of plasma cells whose normal job is to fight off infection and produce proteins called antibodies . When these cells grow abnormally in the marrow they effectively crowd out the normal bone marrow cells – many people have low blood counts when they initially come and see us --- and that’s common for blood cancers .
However , myeloma otherwise is a peculiar disease and causes a lot of other symptoms. So by growing in the bone marrow – centre of the bones , it can secrete various hormones that weaken the bones and can lead to punched out lesions in the bones that we talk about called lytic bone lesions leading to severe pain and high calcium levels
Moving on myeloma is a condition which weakens the immune system and patients often come to us with signs of infection – chest infectuions .
Finally there is this protein produced by the Myeloma cells called the M protein (monoclonal /myeloma protein ) which can cause damage to kidneys and lead to nerve problems in fingers and toes (before treatment even begins )
Now we will focus a little more on this M protein

8. So I want to talk a little more about this mprotein because its quite important – in terms of diagnosis, for following response to treatment and also as it is unusual in blood cancers .
So the normal plasma cell makes this guy on the far left called the immunoglobulin – the top end normally sticks to normally sticks to things like bacteria and viruses and helps us fight infections
In myeloma , we make a lot of this type of protein but it doesn’t work well and doesn’t really help us fight infections very well.
On the upside , it is something we can measure in the blood and sometimes in the urine and its useful to help us diagnose but also very useful in helping us follow the disease ,--- as the disease grows this number might go up but as the disease is treated this should go down and help us monitor response without having to resort to marrows very often,

9. So I want to show you that in a schematic
So I want to show you that in a schematic . So along are the different steps in myeloma – from asytomatic to aggressive myeloma at this end . And this is the M protein on the bottom
So you can see that in the symptomatic phase the M protein is quite low and as the disease become sprogressive the M protein spikes hee=re – patient is put on treatment – protein gradually comes down until it plateaus or disappears and then eventually goes up again . This is the time , this first remission , that there is a lot of focus on how we can deepen this remission and extend it for as long as possible

10. Questions at diagnosis
Do I have Symptomatic Myeloma ?
What is my prognosis /stage etc?
Am I eligible for transplant ?
What Initial treatment ?
Questions I ask myself and questions that you are probably asking yourselves as patients when first diagnosed .
The first question is do I have myeloma that needs to be treated – do I have the symptoms that need to be addressed?
The second question is what is my prognosis and what stage am I at
The third question is am I eligible for this treatment called a stem vell transplant
Last question is what is the best treatment option for me at the start

11. Who needs to be treated – myeloma defining events
CRAB- felt to be related to myeloma
C – high calcium in blood
R – Renal /Kidney dysfunction
A – anaemia
B – bone disease
Now also 60% plasma cells , very high light chain ratio and >1 myeloma lesion on MRI ( SLIM criteria )
Q 1 – not everyone who has myeloma in their marrow needs treatment , there are many patients with smoulsering mueloma who may not develop symptoms for many many years if at all so we don’t treat everyomne . The patients we do treat are those who develop or have at least one of what we call the CREAB criteria – stands for
SLIM criteria

12. Questions at diagnosis
Do I have Symptomatic Myeloma ?
What is my prognosis /stage etc?
Am I eligible for transplant ?
What Initial treatment ?
Questions I ask myself and questions that you are probably asking yourselves as patients when first diagnosed .
The first question is do I have myeloma that needs to be treated – do I have the symptoms that need to be addressed?
The second question is what is my prognosis and what stage am I at
The third question is am I eligible for this treatment called a stem vell transplant
Last question is what is the best treatment option for me at the start

13. So I wanted first to show you how things have changed in myeloma in the last years , this u=is what we call the five year survival curve or the number of people alive with their disease at five years . You can see that this no is quite low only about 20% in the 1970s and nothing really changed Iin the 70s , 80s 90s its only in ther last fifteen years or so that those nos have improved – in 2008 about 50 % alive at years and the graph is old and stops there now its fair to say that that 5 year survival is about 75-80% -- so we are getting better and better and we now have ways to individualise that and help us find out who are the patients who might respond better and who are those a little more at risk of relapsing early

14. so that addresses the first question
So the second question --- what is my prognosis or stage
so the first thing we use is this satging systm stages – all treated the same – simple stGIng system based on blood tests that are routinely done at diagnosis
In the last few years , we have added into the old system a thing called the karyotype which is a test done on the bone marrow plasma cells which looks at the gebetic material of the myeloma plasma cells – we can kind of stratify patients into lower or higher risk groups and give you an idea of your prognosis individually and how you might respond to treatment .

15. Questions at diagnosis
Do I have Symptomatic Myeloma ?
What is my prognosis /stage etc?
Am I eligible for transplant ?
What Initial treatment ?
So that’s the second question answered . Now the next question is am I eligible for transplant

16. The third question is am I eligible to get this treatment called autologous stem vell transplant – touvhed on later
When this treatment was first developed – generally in pts up to the age of 60 or maybe 65 but nowadays we know that it is not really the age that matters but how well a patient is otherwise – you can have a very fit 73 year old who could be be considered firt for transplant , and of course we have the element of patients being able to choose what they want as we have many treatment options now

17. Just wanted to touch a little more on autogolous stem cell transplant and the concept behind it , autologous are cells which have been collected from yourself after having been mobilised with usually chemo and gcsf – a few weeks later – high dose traditional chemotherapy called melphalan and it is the melphalan here that helps the myeloma . The problem with melphalan is that its very toxic and your bone matrrow wouldn’t recover if you didn’t have these stem cells to go back in and find their way to your narrow which gradually recovers from the chemo over abput 14 days , so I made it sound very simple but obviously there are risks

18. Some very real benefits – can afford a much prolonged remission up to years and these pts may even be considered cured

19. Questions at diagnosis
Do I have Symptomatic Myeloma ?
What is my prognosis /stage etc?
Am I eligible for transplant ?
What Initial treatment ?
4th question was what is the best treatment at the beginning of the disease

20. I think this schema gives you an idea of what many of us recommend for patients who might be eligible for transplant, we tend to recommend a few months 3-4 months of treatment at the beginning – transplant – and then to continue a strategy known as maintenance which is to continue a low intensity of treatment long term and we know by using this soryt of plan we can often keep patients in that first remission for a long time --- so as well as getting new drugs we have also changed the way in which we use them which has a definite impact on remission duration and oS

21. Its not very different for patient who cant or don’t wish to undergo a transplant – we tend to prolong this initial phase of treatment to 6-12 months and then move back down into a maintenance phase and can keep people in remission for a long time

22. Considerations in initial treatment
Many new treatments/ drugs
Questions to consider
2 drug /3 drug regimen
Kidney function
Accessibility and ease of administration
( cost )
So lets talk specifically about what drugs to use

23. Treatment options Significant change in last 18 years Before 1999
Autologous stem cell transplant , conventional chemotherapies – melphalan , cyclophosphaimide
Introduction of two very effective classes of medications
– immunomodulatory drugs – IMIDs – thalidomide , lenalidomide and Pomalidomide
- Proteasome inhibitors – Velcade ( Bortezomib) , Kyprolis (Carfilzomib) and Ixazomib
Lets talk specifically about the drugs

24. Both drugs were blockbusters , both drugs work well independently
Before long , the idea of combining both drugs with steroids or other chemo agents – or using the triplet combination rather than either drug combined with dexamethasone .
Three drug combination better than two in many patients --- big trial published only about two years ago which really shows improved survival and improved time to next treatment
Should really be considered in everyone except the most frail of patients who have no medical issues prohibiting use of either drug

25. Supportive medications
Bisphosphonates
Preventative IvIg
Flu Vaccine
Meds to counteract side effects – dvt prevention, anti virals especially with Bortezomib

26. Relapse disease treatment considerations
A lot of drugs available
When to treat – M spike is very sensitive
Side effects of previous medication – neuropathy
Renal function
Patients older – convenience etc

27. Daratumomab
Anti CD38 monoclonal antibody – both alone and in combination
Ireland , difficulties getting it in combination , can only be used in the relapsed setting
We anticipate that it will be moved up to front line as more evidence for its use upfront accumulates – looks very promising
Other drugs in pipeline - multiple drugs approved for myeloma

28. Summary The paradigm has changed in the last ten years
Patients with Myeloma living a lot longer with prolonged periods of remission
More and better treatment options are available
The way we use the drugs are changing --- maintenance
Research ongoing internationally -Continues to improve
??? Soon – Chronic disease , Cure in future ??

29. Questions

30. The good
Sarah Newbury – treatment – orange peel , porter , mutton chops, bleeding and cupping – suffice it to say that it didn’t work very well
Steel shavings , rhubarb , chemicals – urethane
Radiation – top half or bottom half
1850s 1950s – very little treatment agents – survival 6mths
1960s – advent of a drug melphalan 1958– introduction was revolutionary and increased survival to about 2 years , around that time cyclophosphamide cane into use and combining with steroids helped these drugs work better
20 years later - nothing had changed
There are very few cancers that have tripled survival in 15 years but that is what has happened in myeloma .
I want to bring you back to sarah Newbury here , the first patient reported in the medical literature back in 1859,