Genetics and myeloma - Myeloma Infoguide Series Essentials - Myeloma UK
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Genetics and
myeloma
Myeloma
Infoguide Essentials
Series
Genetics Infoguide Feb 2017 Barrs Final.indd 1 14/03/2017 12:32:38This Infoguide has been made possible thanks to the generosity
of Myeloma UK supporters.
To find out how you can support our vital work call 0131 557 3332
or email fundraising@myeloma.org.uk
Myeloma Infoline: 0800 980 3332 or
1800 937 773 from Ireland
www.myeloma.org.uk
Genetics Infoguide Feb 2017 Barrs Final.indd 2 14/03/2017 12:31:22Contents
4 Introduction 29 Genetic subtypes of myeloma
6 What is myeloma? 32 Future directions
9 Treatment for myeloma 34 Medical terms explained
– the basics
38 F
urther information and
11 What is genetics? useful organisations
17 T
ests and investigations 52 About Myeloma UK
to detect genetic changes
54 Information available
in myeloma
from Myeloma UK
20 Genetic changes in the
55 Other publications
development of myeloma
56 We need your help
24 T
ypes of genetic abnormalities
that can occur in myeloma
Disclaimer: The information in this Infoguide is not meant to replace the advice of your medical team.
They are the best people to ask if you have questions about your individual situation.
This publication is intended for a UK audience. It therefore may not provide relevant or accurate information
for a non-UK setting.
Infoline: 0800 980 3332 3
Genetics Infoguide Feb 2017 Barrs Final.indd 3 14/03/2017 12:31:22Introduction
This Infoguide has been written for myeloma patients. It
may also be helpful for their families and friends.
It aims to:
■■ Help you understand more Some of the more technical or
about what genetics is unusual words appear in bold the
■■ Provide you with information first time they are used and are
about the types of genetic described in the Medical terms
changes that can occur in explained section on page 34.
myeloma
■■ Answer some of the questions
you may have about how the
genetics of myeloma may
influence future treatment
4 www.myeloma.org.uk
Genetics Infoguide Feb 2017 Barrs Final.indd 4 14/03/2017 12:31:22For more information
Myeloma UK provides a wide The Myeloma Infoline is open
range of information covering from Monday to Friday, 9am to
all aspects of the treatment and 5pm and is free to phone from
management of myeloma. anywhere in the UK and Ireland.
For a full publication list Information and support about
visit www.myeloma.org.uk/ myeloma is also available around
publications the clock at www.myeloma.org.uk
To order your free copies contact
Myeloma UK. Our information is
also available to download at
www.myeloma.org.uk
To talk to one of our Myeloma
Information Specialists about
any aspect of myeloma, call
the Myeloma Infoline on
0800 980 3332 or
1800 937 773 from Ireland.
Infoline: 0800 980 3332 5
Genetics Infoguide Feb 2017 Barrs Final.indd 5 14/03/2017 12:31:23What is myeloma?
Myeloma, also known as multiple myeloma, is a type of
cancer arising from plasma cells that are normally found
in the bone marrow. Plasma cells are a type of white
blood cell which form part of the immune system.
Normal plasma cells produce of paraprotein that myeloma is
different types of antibodies diagnosed and monitored.
(also called immunoglobulins) to Bone marrow is the ‘spongy’
help fight infection. In myeloma, material found in the centre of
the plasma cells become the larger bones in the body. As
malignant and release a large well as being home to plasma
amount of a single type of cells, the bone marrow is where
antibody, known as paraprotein, blood cells (red blood cells,
which has no useful function. It is white blood cells and platelets)
often through the measurement are made (see Figure 1).
RED WHITE
BLOOD CELLS BLOOD CELLS
lymphocyte plasma
cell
monocyte
blood
stem cell neutrophil
BONE eosinophil
MARROW
basophil
PLATELETS
Figure 1. Bone marrow – responsible for the production of blood cells
6 www.myeloma.org.uk
Genetics Infoguide Feb 2017 Barrs Final.indd 6 14/03/2017 12:31:23These all originate from blood Myeloma most commonly occurs
stem cells. Plasma cells normally in people later in life i.e. over
make up less than 5% of the total the age of 65. However, some
blood cells in the bone marrow. myeloma patients are younger. It
Myeloma affects multiple is also slightly more common in
places in the body (hence why men than in women.
it is sometimes referred to as The causes of myeloma are not
‘multiple myeloma’) where bone fully understood but it is believed
marrow is normally active i.e. to be caused by an interaction of
within the bones of the spine, both genetic and environmental
pelvis, rib cage and the areas factors.
around the shoulders and hips. There are thought to be multiple
The areas usually not affected are environmental factors which may
the extremities – the hands and increase the risk of developing
feet – as the bones here do not myeloma. Exposure to specific
contain bone marrow. chemicals, radiation, viruses and
Most of the symptoms and a weakened immune system are
complications of myeloma are considered important trigger
caused by a build-up of the factors.
abnormal plasma cells (often It is likely that myeloma develops
called myeloma cells) in the bone when a susceptible (at risk)
marrow and the presence of individual has been exposed to
paraprotein in the body. one or probably several of these
Common problems include bone factors.
pain, bone fractures, tiredness There is a slight tendency for
due to anaemia, frequent or myeloma to occur in families.
recurrent infections (such as Although rare, this suggests
chest infections, urinary tract there may be inherited factors
infections and shingles), kidney in myeloma. This alone is not
damage and hypercalcaemia. enough to cause myeloma but
Infoline: 0800 980 3332 7
Genetics Infoguide Feb 2017 Barrs Final.indd 7 14/03/2017 12:31:23may make an individual at a Basic facts
slightly higher risk of developing ■■ There are approximately
myeloma - other environmental 5,500 people diagnosed with
factors also need to have an myeloma every year in the UK
impact before it develops.
■■ There are approximately 17,500
In the majority of cases, however, people living with myeloma in
the causes of myeloma are not the UK at any one time
fully understood’ and are likely
to be unique to each patient. ■■ Myeloma accounts for 15%
of blood cancers and 2% of
Much research is ongoing into cancers generally
the biology and genetics of
myeloma to determine the ■■ Myeloma mostly affects people
factors responsible for its onset aged 65 and over but it has
and progression. been diagnosed in people as
young as 20
For more information see the
Is myeloma an inherited cancer?
Infosheet from Myeloma UK.
8 www.myeloma.org.uk
Genetics Infoguide Feb 2017 Barrs Final.indd 8 14/03/2017 12:31:23Treatment for myeloma – the basics
Treatments for myeloma can be very effective at
controlling the disease, reducing symptoms and
improving quality of life but, as yet, they are not
curative. In general, treatment is given to:
■■ Reduce the levels of Treatment for myeloma is often
myeloma as far as possible most effective when two or
■■ Control the myeloma for more drugs, with different but
as long as possible complementary mechanisms of
action, are given together.
■■ Control the myeloma if it
returns (relapse) Before starting treatment, each
option must be considered
■■ Relieve the symptoms and carefully so that the benefits of
reduce the complications treatment are weighed against
the myeloma is causing the possible risks of side-effects.
■■ Improve quality of life In most patients, overall health,
■■ Prolong life age, fitness and any previous
treatments will be taken into
Not everyone diagnosed with
account.
myeloma will need to start
treatment immediately – the Treatment is usually given over
timing of treatment will a number of weeks which may
depend on a number of factors or may not be followed by a rest
including the speed at which the period. This pattern constitutes
paraprotein level is rising. one cycle of treatment and a series
of treatment cycles is referred to
as a course of treatment.
Infoline: 0800 980 3332 9
Genetics Infoguide Feb 2017 Barrs Final.indd 9 14/03/2017 12:31:23Supportive treatments are
also commonly prescribed
to help prevent or manage
potential side-effects of
treatment combinations
and also treat the symptoms
and complications of
myeloma.
10 www.myeloma.org.uk
Genetics Infoguide Feb 2017 Barrs Final.indd 10 14/03/2017 12:31:24What is genetics?
Genetics is the study of genes which are the sets of
instructions that determine how each cell in the body
develops and grows.
We inherit our genes from both each gene in every cell, with the
our parents but they can change exception of the chromosomes
over time. Genes are responsible which determine the biological
for determining certain inherited sex of a baby (known as the X
traits such as eye colour and hair and Y chromosomes).
colour but they also control all
processes within cells. DNA
Genes are made up of
What are genes? deoxyribonucleic acid (DNA),
Genes are sets of instructions which stores genetic information.
that determine how each cell DNA is tightly wound into a
in your body develops and shape known as a double helix,
grows. They are responsible for which looks a bit like a ladder.
determining characteristics such Each ‘rung’ of the ladder is made
as hair colour and eye colour. up of specific sequences (known
as base pairs) that contain the
Chromosomes instructions or ‘genetic code’. The
four chemical bases (‘rungs’) are
Genes are packaged
adenine, cysteine, thymine and
together into bundles called
guanine (shortened to A, C, T and
chromosomes. Each cell within
G). These are repeated in various
the body normally has 23 pairs
different combinations, forming
of chromosomes. One of the
the code that instructs our body
chromosomes from each pair
how to function. Together genes
is inherited from the mother
and DNA make up the blueprint
and one from the father which
of life (see Figure 2).
means there are two copies of
Infoline: 0800 980 3332 11
Genetics Infoguide Feb 2017 Barrs Final.indd 11 14/03/2017 12:31:24CELL DNA
GENE
chemical
base pairs
adenine
thymine
CHROMOSOME cytosine
guanine
Figure 2. Chromosome overview
Figure 1. An overview of where chromosomes fit into the cell
Figure: MUK25_chromosome_overview-2COL
How do genes work? ©www.myeloma.org.uk
These include: design by www.blink.biz
Genes control how a cell works ■■ Providing structure and
by making proteins that have a support to a cell
specific function within the body. ■■ Controlling cell growth and
Each gene contains a specific making new cells
‘code’ (made up of different
combinations of A, C, T and ■■ Acting as a messenger within a
G bases) which provides the cell or between different cells,
information needed to make a tissues or organs
particular protein, in a particular ■■ Helping to protect the body
cell, at a particular time. from viruses and bacteria
Proteins are required for a variety
of important roles in the body’s
cells, tissues and organs.
12 www.myeloma.org.uk
Genetics Infoguide Feb 2017 Barrs Final.indd 12 14/03/2017 12:31:24As a result, the role of some Genetic changes have two origins
genes is to control how quickly and can occur at any time during
new cells grow, how long they our lifetime. One of these origins
live for or when then die. This is a is spontaneous, where change
tightly controlled process, which occurs as a result of being
enables the body to grow, heal exposed to certain chemicals or
and repair itself. external factors such as alcohol,
smoking (tobacco) or asbestos.
What happens if the genetic These are known as acquired. The
code changes? other origin is inherited, where
genetic changes can be passed
It is possible for the DNA
on from one or both of our
sequence within a gene to
parents. These genetic changes
unexpectedly and unintentionally
are discussed further below using
change which means the
mutations as an example.
sequence differs from its
original code. These can occur
as changes to the DNA code Acquired mutations
itself, called mutations, or as Acquired mutations are errors to
changes to larger segments of DNA which occur at some point
DNA within chromosomes, called during a person’s life and only
translocations, deletions or gains. occur in certain cells within the
Genetic changes can cause body. Mutations can be caused
diseases, conditions and cancers by environmental factors such
to develop because the change as a person’s diet and lifestyle,
in code changes the genetic or as a mistake made during cell
instructions they carry. This can division.
result in the wrong protein being Cell division is a process where
made, or cause an imbalance in a cell is required to produce an
the amount of normal proteins exact copy of itself and all of its
that are made. DNA (see Figure 3). This process
allows cells to multiply which is
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Genetics Infoguide Feb 2017 Barrs Final.indd 13 14/03/2017 12:31:24necessary for the body to grow, permanent change in the genetic
develop and repair itself. material. This means every time
Sometimes completely random a cell divides and copies, it is an
and unplanned mistakes are made opportunity for a fault to occur.
in the new cell, which can lead to a The number of these genetic
changes builds up over time,
which is why there is a higher risk
1 × parent cell
of cancer as we get older.
46 chromosomes
(23 pairs)
Inherited mutations
DNA
REPLICATION Inherited mutations are changes
within the genetic material that
all chromosomes can be passed on from our
duplicate
parents. These mutations are
present throughout a person’s
life in every cell in the body.
chromosomes
They are also known as germline
separate mutations because they are
CELL
present in cells known as germ
DIVIDES cells (the parent’s egg or sperm
cells).
2× 23
daughter pairs Inherited mutations within certain
cells each
genes are known to increase
FURTHER DIVISION
the chances of developing
certain cancers and diseases, for
example inheriting faulty BRCA1
and BRCA2 genes is known to
increase the risk of developing
4 × daughter cells
certain cancers including breast
Figure 3. The process of cell division
cancer.
14 www.myeloma.org.uk
Genetics Infoguide Feb 2017 Barrs Final.indd 14 14/03/2017 12:31:24Acquired and inherited relative who has myeloma, the
mutations in myeloma risk is 10 in 100,000. It is also
The cause of myeloma is not fully important to remember that if
understood, but it is thought people do inherit these genetic
to involve both environmental variations, it doesn’t mean that
(acquired) and genetic (inherited) they will develop myeloma. It
factors. is certain that a combination of
Population studies in myeloma other genetic and environmental
have shown that immediate factors are needed for myeloma
family members have a slight to develop.
increased risk of developing
myeloma, however, myeloma For more information see the
is not an inherited cancer. It Is myeloma an inherited cancer?
Infosheet from Myeloma UK.
is thought the increased risk
is because there are certain
inherited genetic variations
More is now known about
which are known to increase the
the types of acquired genetic
chances of a person developing
mutations that occur in myeloma
myeloma. However these
and further details can be found
inherited genetic variations
on page 24.
are only a small part of the
puzzle and the increased risk of
someone who is a close relative Why researchers are interested
of a myeloma patient also in genetic changes in myeloma
developing myeloma remains The causes of myeloma are not
very small. fully understood; however, we do
In the general population the know that the onset of myeloma
risk of developing myeloma is is a complex multistep process
5 in 100,000 and in individuals and is driven by genetic changes
who have an immediate blood that occur in myeloma cells.
Infoline: 0800 980 3332 15
Genetics Infoguide Feb 2017 Barrs Final.indd 15 14/03/2017 12:31:24Studying the changes that occur
in myeloma cells is important in
order to understand:
■■ How myeloma begins
■■ How myeloma progresses
■■ Why some myeloma cells
become resistant to treatment
■■ How treatment can be tailored
to patients depending on their
genetic subtype of myeloma
(see page 31 for more details)
Understanding the biology
and genetics of myeloma helps
doctors and researchers to
better understand how myeloma
behaves which allows them to
identify new targets for treatment
within the myeloma cell.
16 www.myeloma.org.uk
Genetics Infoguide Feb 2017 Barrs Final.indd 16 14/03/2017 12:31:24Tests and investigations to detect
genetic changes in myeloma
It is important to identify the genetic changes that
occur in myeloma cells over time, but also by looking
at tissue samples to better understand the genetic
differences between myeloma patients and people who
do not have myeloma. To do this, careful examination
and testing of patient’s tissue samples, which is only
performed in a specialised laboratory, is required.
Previously, the NHS did not However, information regarding
routinely perform genetic tests the phenotype of patient’s
as part of standard treatment myeloma is not currently used
and care. However, in February to tailor treatment regardless
2016, NICE (National Institute of whether or not patients have
for Health and Care Excellence) FISH testing.
published a myeloma guideline
which recommends that all Collection of samples
patients should have access to
In order to examine and identify
genetic testing by Fluorescence
genetic changes that occur in
in situ Hybridisation (FISH) (see
myeloma, two types of tissue
page 19) at diagnosis in order to
samples are collected from
identify any genetic risk factors
patients, these are:
and to better understand the
phenotype (characteristics) of ■■ A blood sample (to collect
their myeloma cells. DNA from a normal cell
i.e. not a myeloma cell)
Some patients might have access
to genetic testing through a ■■ A bone marrow sample
clinical trial where samples (to collect DNA from a
provided by patients, with their myeloma cell)
consent, are used in research.
Infoline: 0800 980 3332 17
Genetics Infoguide Feb 2017 Barrs Final.indd 17 14/03/2017 12:31:25The samples are then sent to the highest standard to preserve
a laboratory that specialises in the quality of the sample for
genetic testing where the DNA research and allow comparisons
is extracted from the samples to be made between samples.
and used for testing. These
The UK Myeloma Biobank
tests identify genetic changes in
also allows researchers to test
chromosomes or genes within
samples from the same patient
the myeloma cells compared to
over time, for example to study
normal cells.
the genetic changes that occur at
Storage of patient samples one stage of myeloma compared
to another stage, and from one
As a rare cancer, there are a patient to another. This will allow
limited number of myeloma researchers to better understand
patient samples available so it how myeloma progresses in an
is important to learn as much individual or between different
as possible from the samples
subgroups of patients and help
collected. Samples are usually
to develop new ways to treat
collected though clinical trials,
patients.
and are stored in a biobank,
which is an organised system for
Types of genetic tests
collecting and storing biological
samples. There are several different tests
that detect different types of
At The Institute of Cancer
genetic errors in cells however
Research (ICR) in London there
the most common ones used in
is a central UK-wide biobank
myeloma are:
specifically for myeloma samples,
known as the UK Myeloma Karyotyping – this is a test used
Biobank. The UK Myeloma to examine the number and
Biobank ensures that all of the appearance of chromosomes
patient samples are collected and in order to ensure the correct
stored in the same way and to number of chromosomes are
18 www.myeloma.org.uk
Genetics Infoguide Feb 2017 Barrs Final.indd 18 14/03/2017 12:31:25present and to determine if the the cell. These profiles can be
structure of each chromosome used to distinguish between
appears normal. cells that are actively dividing
Fluorescence in-situ or not, and to show how genes
hybridisation (FISH) – involves within cells react to a particular
staining the chromosomes with a treatment.
fluorescent marker to detect and Next generation sequencing
localise the presence or absence – this is a technique that can
of specific DNA sequences on determine the precise sequence
a chromosome. When stained, of thousands of chemical bases
chromosomes look like strings (A, G, C and T) within the DNA
with light and dark bands which of cells. This provides a very
can be examined under the high level of detail and could
microscope for small or subtle potentially be used for genetic
abnormalities. FISH testing is screening in myeloma (test
more sensitive at detecting healthy people for signs of
the genetic mutations found in myeloma or to see if they are at
myeloma than karyotyping. risk of developing it in the future).
Over the last few years, newer GEP and next generation
techniques have been developed sequencing are only used in
which are available in specialised research laboratories at the
research laboratories and allow a moment because they require
much more in-depth and detailed skilled technicians to perform,
analysis. These are: complex analysis of the data
produced and are very expensive.
Gene expression profiling However, research is ongoing
(GEP) – this is a technique to develop cheaper and quicker
that measures the activity of tests that will identify genetic
thousands of genes in a cell all errors in myeloma cells, which
at the same time, creating a may allow for routine testing in
snapshot of the activity inside clinics.
Infoline: 0800 980 3332 19
Genetics Infoguide Feb 2017 Barrs Final.indd 19 14/03/2017 12:31:25Genetic changes in the development
of myeloma
Myeloma is a type of cancer arising from plasma cells,
which are a type of white blood cell normally found in
the bone marrow and form part of the immune system.
In myeloma, a number of Approximately 1 in 100 MGUS
genetic errors occur during patients a year will go on to
the development of plasma develop myeloma. The criteria
cells. These genetic errors can used to diagnose MGUS is shown
build up and make the cells in Figure 4.
more susceptible to becoming MGUS however is not the only
abnormal. These errors, in turn, preceding stage of active
change the genetic instructions myeloma. Smouldering myeloma
contained within the cells which (also known as asymptomatic
enables the plasma cells to myeloma) is an early form
multiply uncontrollably. It is of myeloma, which usually
this process of uncontrollable progresses at a slow rate, and like
multiplication of the plasma cells MGUS, does not usually require
that progress to myeloma. treatment, however MGUS and
smouldering myeloma patients
Preceding stages of myeloma will be closely monitored.
It is now known that all The genetic similarities and
myeloma patients have a non/ differences between MGUS,
pre-cancerous condition called smouldering myeloma and active
monoclonal gammopathy of myeloma is a large focus for
undetermined significance research in myeloma in order to
(MGUS) before they develop determine what underpins the
myeloma. MGUS patients are progression from one to another.
monitored but do not require
Research to date has identified
treatment and not all MGUS
that MGUS, smouldering
patients will develop myeloma.
20 www.myeloma.org.uk
Genetics Infoguide Feb 2017 Barrs Final.indd 20 14/03/2017 12:31:25myeloma and active myeloma It is hoped that a better
share common chromosome understanding of the genetic
abnormalities but it is still not changes that occur will help
fully understood why some to identify new targets for the
MGUS patients go on to develop treatment of myeloma in the
myeloma and some don’t and future and find ways to prevent
why this occurs quite quickly for MGUS and smouldering myeloma
some patients and more slowly patients from progressing to
for others. Researchers have myeloma, or at least to identify
however identified that myeloma which MGUS and smouldering
cells gain more genetic mutations myeloma patients are more likely
as MGUS progresses to myeloma. to develop myeloma, and when.
MGUS Smouldering myeloma Active myeloma
A paraprotein A paraprotein level in Paraprotein in the
level in the blood the blood of greater blood and/or urine.
of 30g/L or less than 30g/L Serum free light chain
ratio greater than or
equal to 100
Less than 10% Between 10 - 60% Greater than 60%
plasma cells in plasma cells in the plasma cells in the
the bone marrow bone marrow bone marrow
No organ No symptoms or Evidence of symptoms
impairment i.e. organ impairment and organ damage
normal kidney i.e. normal kidney such as kidney
function and function and no damage, anaemia and
no anaemia. anaemia and no bone evidence of one or
Does not require lesions. Does not more bones lesions -
treatment require treatment requires treatment
Figure 4. The criteria used to diagnose MGUS, smouldering
myeloma and active myeloma. Infoline: 0800 980 3332 21
Genetics Infoguide Feb 2017 Barrs Final.indd 21 14/03/2017 12:31:25For more information see the Each cell within one of these
MGUS and Smouldering myeloma clones is genetically identical,
Infosheets from Myeloma UK. but different clones differ
genetically to each other. The
genetic differences in one clone
Evolution of myeloma cells can make these myeloma cells
Recent studies show that a grow faster than the myeloma
patient’s myeloma cells are not cells in other clones, becoming
all genetically identical at a given stronger and more aggressive
time. Some myeloma cells may and resistant to treatment.
acquire further genetic changes This slight genetic variation
over time, creating several sets of between groups of cells is
myeloma cells known as clones. thought to be one of the main
This concept is known as ‘clonal causes of relapse in patients,
evolution’ (see Figure 5). when one or some of the clones
multiplication multiplication
and further and further
mutation multiplication mutation mutation
normal abnormal
cells cell abnormal
clones
new new subclone
subclone
multiplication
TREATMENT
and further
mutation
susceptible resistant clones survive
clones killed and eventually will new
start to multiply subclone
Figure 5. Clonal evolution of myeloma cells.
22 www.myeloma.org.uk
Genetics Infoguide Feb 2017 Barrs Final.indd 22 14/03/2017 12:31:25become resistant to treatment.
Different clones can become
resistant to different treatments
and if this occurs, it can make the
patient’s myeloma more difficult
to treat.
The next sections of this
Infoguide will discuss what is
known about the types of genetic
changes that are acquired during
the development of plasma cells.
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Genetics Infoguide Feb 2017 Barrs Final.indd 23 14/03/2017 12:31:25Types of genetic abnormalities
that can occur in myeloma
The most common genetic errors that occur in myeloma
are changes to chromosomes, which are known as
cytogenetic abnormalities. Cytogenetics is the study of
the structure and function of chromosome.
Other common genetic changes The two main types of
that occur in myeloma are chromosome changes that can
mutations (discussed previously), occur are:
changes to genes that control
Alterations in chromosome
cell growth and changes to gene
number
activity i.e. genes being switched
on or off. Changes to the number of
chromosomes (each normal
Chromosome abnormalities cell in the body has 23 pairs of
chromosomes) is a common
Many cytogenetic changes that genetic abnormality that
occur in myeloma are caused occurs in myeloma. One type
by alterations in chromosomes. of chromosome change is
A change in the number, size called hyperdiploidy which is
or structure of chromosomes when myeloma cells have more
can affect the arrangement of than two copies of a particular
the genetic information within a chromosome.
gene - changes to these genes
can affect the instructions given Alterations in chromosome
to the cells and therefore, in turn structure
determine the behaviour of the During plasma cell development,
cell. chromosomes go through
Different types of chromosome the process of breaking and
abnormalities affect genes re-joining again. However,
differently. in myeloma sometimes the
24 www.myeloma.org.uk
Genetics Infoguide Feb 2017 Barrs Final.indd 24 14/03/2017 12:31:25chromosomes do not always re-join ■■ Chromosome gain
again correctly. This can happen (duplication) – is when a
in a number of different ways (see chromosome has acquired
Figure 6): an additional part of another
■■ Chromosome deletion – is when chromosome. An example of
a section of a chromosome is this in myeloma is 1q gain -
missing. Common chromosome where a part of chromosome
deletions in myeloma are del(13q) 1 has been gained so there
and del(17q) where a part of are more than the normal
chromosome 13 or chromosome two copies.
17 respectively has been deleted
DELETION DUPLICATION TRANSLOCATION
3 3
1 1 1 1 1 1
2
Figure 6. Chromosome abnormalities detected by FISH testing.
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Genetics Infoguide Feb 2017 Barrs Final.indd 25 14/03/2017 12:31:25■■ Chromosome translocation – is Lots of research is focusing
when part of a chromosome on identifying which genes
has switched with a different are involved in controlling cell
chromosome. In myeloma, growth in myeloma and if and
the common translocation how they change over time. It is
abnormalities that occur are hoped this type of research will
between chromosome 4 help to develop new myeloma
and 14, known as t(4; 14) and treatments that could target this
between chromosome 11 and process in myeloma cells to help
14, known as t(11; 14) destroy myeloma cells.
Changes in genes that control Changes in gene activity
cell growth through epigenetic changes
As well as chromosomal Although all cells in the body
abnormalities, other genetic contain the same genes, different
changes can occur in myeloma genes are switched on in different
cells which influence the cells depending on their function.
development and progression This is known as gene expression.
of myeloma. Some mutations Genes can be switched on and
can involve genes that control off in different cells i.e. they can
cell growth and survival. These be active in some cells but not
mutations can cause genes others.
that regulate cell growth to External changes to DNA can
be switched on or off. When also turn genes on or off – this
this happens the myeloma does not change the underlying
cells are allowed to multiply genetic code (sequence of
uncontrollably. The next section DNA) but it does affect how
of the Infoguide talks about genes work, and how they are
how these changes might guide controlled and expressed.
treatment.
26 www.myeloma.org.uk
Genetics Infoguide Feb 2017 Barrs Final.indd 26 14/03/2017 12:31:25These are known as epigenetic Histone deacetylase inhibitors
changes. To carry out gene expression,
Epigenetic changes can be a cell must control the coiling
influenced by several factors and uncoiling of DNA around
including the environment proteins called histones. Histone
(e.g lifestyle), the patient’s deacetylases are enzymes, which
age and stage of myeloma. In change the way histones bind to
myeloma, at least three types DNA within cells and in doing so,
of epigenetic changes are they cause certain genes to be
thought to play a role in altering “switched off” (see Figure 7).
the activity of genes involved Myeloma cells contain an excess
in controlling the growth and of histone deacetylases. This
survival of myeloma cells. causes many of the genes
Understanding the epigenetic involved in controlling cell growth
changes in myeloma, in particular to be switched off, which in turn
an epigenetic mechanism known allows myeloma cells to multiply
as histone modification, has out of control.
led to the development of new Histone deacetylase inhibitor
treatments including a new drugs work by blocking the
class of drug known as histone action of histone deacetylase in
deacetylase inhibitors. myeloma cells which prevents
them from growing and surviving.
Infoline: 0800 980 3332 27
Genetics Infoguide Feb 2017 Barrs Final.indd 27 14/03/2017 12:31:25Panobinostat (Farydak®) is a
For more information see the
type of histone deacetylase Panobinostat and myeloma
inhibitor drug that has been Infoguide from Myeloma UK.
approved for use in the NHS
for relapsed and/or refractory
myeloma patients.
REPRESSION OF GENE EXPRESSION
condensed
acetyl
deacetylation
acetylation DNA histone by histone
deacetylase
(HDAC) enzyme
DRUG
relaxed
histone deacetylase
inhibitors block
deacetylation and
ACTIVATION OF GENE EXPRESSION keep genes active
Figure 7: Mechanism of action
28 www.myeloma.org.uk
Genetics Infoguide Feb 2017 Barrs Final.indd 28 14/03/2017 12:31:25Genetic subtypes of myeloma
The different types of genetic abnormalities that occur
in myeloma allows for myeloma to be classified into
subtypes.
The most common myeloma ‘High-risk’ myeloma
genetic subtypes are: Certain genetic abnormalities are
■■ t(4;14) associated with a more active or
more difficult to treat myeloma,
■■ del(13q) which is known as ‘high-risk’
■■ del(17p) myeloma. Patients with high-
risk myeloma do not normally
■■ 1q21gain respond as well to treatment
■■ t(11;14) and are more likely to relapse
more quickly. The cytogenetic
■■ Hyperdiploidy abnormalities associated with
Each genetic subtype are high-risk myeloma are:
defined by various chromosome ■■ del17p
abnormalities and have their own
■■ t(4;14)
distinctive features, which may
influence not only how quickly ■■ t(14;16)
patient’s myeloma develops but ■■ 1q gain
how well they respond to certain
It is estimated that 20% of
treatments and how quickly they
newly diagnosed patients have
become refractory to them. As
high-risk myeloma and have one
such, genetic abnormalities have
or more of the chromosomal
the potential to be powerful
abnormalities listed above.
prognostic markers in myeloma.
Having more than one adverse
chromosome abnormality
Infoline: 0800 980 3332 29
Genetics Infoguide Feb 2017 Barrs Final.indd 29 14/03/2017 12:31:25is associated with a less they are unlikely to respond to.
favourable prognosis. After each Currently there is much ongoing
treatment, the proportion of research to work out the best
high-risk patients is thought to
approaches to overcome the
increase because new genetic
different subtypes of myeloma.
abnormalities can occur within
It is known that certain
myeloma cells at relapse.
treatments are more suitable to
Having high-risk myeloma does overcome high-risk features, for
not necessarily mean that there example, the use of bortezomib
aren’t treatment options available (Velcade®) is a more effective
to patients, it does however treatment than thalidomide for
mean that high-risk typically
patients with the t(4;14) subtype
respond less favourably to
of myeloma.
certain treatments and periods
of plateau or remission may be Due to an increased
shorter. understanding of the genetic
changes in myeloma and the
There are advantages and
disadvantages for patients to development of new diagnostic
learn that they have high or tools to detect them, clinical trials
low risk myeloma – for patients are looking at new approaches,
to learn they have high-risk such as stratified medicine, for
myeloma can make an already myeloma patients, in particular
upsetting time even more for high-risk patients. High-
anxious. Similarly it can guide risk patients may require more
more stratified treatment for aggressive treatment, or different
patients (see page 31) which combinations of treatment,
means patients can potentially to keep their myeloma under
avoid side-effects to treatments control for as long as possible.
30 www.myeloma.org.uk
Genetics Infoguide Feb 2017 Barrs Final.indd 30 14/03/2017 12:31:25Using genetics to guide
stratified medicine
Stratified medicine is a treatment
approach that aims to tailor
treatment to an individual patient,
for example based on their
genetic subtype of myeloma.
It predicts the treatments that
different subtypes of patients
might respond to, and how their
myeloma is likely to progress or
change over time.
Stratified medicine aims both to
improve outcomes for patients
and improve patients’ quality
of life as in theory it prevents
patients from receiving
treatment that will not be
effective at controlling their
myeloma, and spared from
side-effects to treatments that
are unlikely to work. Stratified
medicine aims to improve current
treatment schedules for patients
who at the moment are often
treated with a ‘one size fits all’
approach. The ultimate aim of
stratified medicine is to give
the right treatment, to the right
patient, at the right time.
Infoline: 0800 980 3332 31
Genetics Infoguide Feb 2017 Barrs Final.indd 31 14/03/2017 12:31:26Future directions
Over the last few years, advances in genetic research
and newer genetic testing techniques, have led to an
improved understanding of how myeloma develops,
progresses and how well it will respond to certain
treatments.
Advances in genetic techniques cell growth and survival. These
Newer techniques such as next findings have led to a different
generation sequencing have type of drug being researched
allowed an unprecedented for use in myeloma which
detailed insight into the genetic specifically targets the RAS
changes that occur in myeloma family abnormalities and kills the
cells. This has allowed the cells carrying this abnormality.
identification of genes that could By using next generation
potentially be targeted by drugs sequencing techniques, other
to specifically kill myeloma cells. abnormalities may also be
identified as potential targets for
A recent research study new myeloma treatments in the
carried out at the ICR used future.
next generation sequencing to
examine myeloma cells from
Advances in understanding how
samples donated by myeloma
myeloma begins
patients enrolled on the Myeloma
XI clinical trial. Findings from this Another area of research is
study showed that nearly 50% focusing on understanding the
of newly diagnosed patients genetic differences between
commonly had an abnormality in MGUS, smouldering myeloma
a group of genes known as the and myeloma. It is hoped that
RAS family. These genes code for ongoing research will begin to
proteins that increase myeloma improve understanding about
how the preceding stages of
32 www.myeloma.org.uk
Genetics Infoguide Feb 2017 Barrs Final.indd 32 14/03/2017 12:31:26myeloma, either from MGUS or Advances in how myeloma
smouldering myeloma, progress progresses
to myeloma. It is hoped this will Understanding the progression
lead to the development of new of myeloma has significantly
drugs which will target specific improved in the last five years.
mutations at these stages to Through the discovery of clonal
prevent or delay the progression evolution, we now know that
to myeloma. within an individual patient not all
Other areas of research are myeloma cells are identical and
focusing on identifying inherited several subsets of myeloma cells
genetic variants that are slightly with different mutations exist.
increased in families of myeloma This means that a drug which
patients. These subtle genetic targets a specific mutation, may
variants may effect cell processes only treat one clone, leaving
that can go wrong during the other clones to survive and
development of myeloma; potentially go on to cause a
however, further research is relapse.
required to confirm this. These The focus of current research is
discoveries are adding to our how the genetics of myeloma
knowledge about how myeloma cells within an individual change
first develops and will potentially over time and at the time of
lead to better ways of diagnosing, relapse, as well as how myeloma
treating or preventing myeloma. cells change in the presence of
treatment, in order to identify and
help design treatment to prevent
relapse and maintain long-term
remission.
Infoline: 0800 980 3332 33
Genetics Infoguide Feb 2017 Barrs Final.indd 33 14/03/2017 12:31:26Medical terms explained
Anaemia: A condition in which Clinical trial: A research study of
the amount of haemoglobin in new or existing treatment that
the blood or the number of red involves patients. Trials may be
blood cells is below the normal designed to find better ways to
levels, causing shortness of prevent, detect, diagnose, or treat
breath, weakness and tiredness. a condition or to answer specific
Antibodies (immunoglobulins): scientific questions.
Proteins found in the blood Cytogenetics: The study of the
produced by cells of the immune structure and function of cells,
system, called plasma cells. Their particularly chromosomes.
function is to bind to substances Deoxyribonucleic acid (DNA):
in the body that are recognised Stands for deoxyribonucleic acid.
as foreign, such as bacteria and A molecule that contains the
viruses (known as antigens), instructions an organism needs to
enabling other cells of the develop, live and reproduce. DNA
immune system to destroy and is found in every cell of the body.
remove them.
Enzyme: A protein which
Bone marrow: The soft, spongy increases the rate of chemical
tissue in the centre of bones that changes in the body.
produces blood cells.
Farydak® (panobinostat): A type
Bortezomib (Velcade®): A of histone deacetylase inhibitor
type of proteasome inhibitor drug which is given orally.
drug which is given either as
an intravenous infusion or Fluorescence in situ
subcutaneous injection. Hybridisation (FISH): A test
used to detect chromosomal
Chromosomes: Structures in abnormalities in myeloma cells.
which the DNA is packaged
within a cell.
34 www.myeloma.org.uk
Genetics Infoguide Feb 2017 Barrs Final.indd 34 14/03/2017 12:31:26Genes: Strands of DNA which Immunoglobulins (antibodies):
act as a set of instructions to Proteins found in the blood
make molecules called proteins. produced by cells of the immune
Together make up the blueprint system, called plasma cells. Their
of life that determines how function is to bind to substances
the body develops, grows and in the body that are recognised
functions. as foreign, such as bacteria and
Genetic: Relating to genes or viruses (known as antigens),
heredity. enabling other cells of the
immune system to destroy and
Histone deacetylase (HDAC) remove them.
inhibitor: A type of drug used
to block the action of histone Malignant: A term for cancerous
deacetylase in myeloma cells, cells which have the ability to
preventing their growth and spread.
survival. Monoclonal Gammopathy of
Hypercalcaemia: A higher than Undetermined Significance
normal level of calcium in the (MGUS): A non-cancerous
blood, which may cause loss of condition in which low levels
appetite, nausea, thirst, fatigue, of paraprotein are present in
muscle weakness, restlessness the blood. Patients do not have
and confusion. symptoms but have an increased
risk of developing myeloma.
Immune system: The complex
group of cells and organs National Institute for Health and
that protect the body against Care Excellence (NICE): A public
infection and disease. body responsible for assessing
the clinical and cost-effectiveness
of new drugs or treatment
combinations for use on the NHS
in England and Wales.
Infoline: 0800 980 3332 35
Genetics Infoguide Feb 2017 Barrs Final.indd 35 14/03/2017 12:31:26Panobinostat (Farydak®): A type Quality of life: A term that refers
of histone deacetylase inhibitor to a person’s level of comfort,
drug which is given orally. enjoyment, and ability to pursue
Paraprotein: An abnormal daily activities. It is a measure of
antibody (immunoglobulin) an overall sense of wellbeing.
produced in myeloma. Red blood cells: A type of blood
Measurements of paraprotein cell which transports oxygen
in the blood can be used to around the body.
diagnose and monitor the Refractory: Disease that has
disease. Also known as M protein. failed to respond to treatment or
Plasma cells: A type of white stopped responding to treatment
blood cell that produce Relapse: The point where disease
antibodies (immunoglobulins) to returns or becomes more active
fight infection. after a period of remission or
Platelets: A type of blood cell plateau (often referred to as
which are involved in blood stable disease).
clotting. Remission: The period following
Prognosis: The probable treatment when myeloma cells
outcome or course of a disease. and paraprotein are no longer
Prognostic marker: A detectable, and there are no
characteristic that gives clinical symptoms of myeloma.
an indication of the likely Side-effects: The undesired
progression of a disease. effects caused by a drug or
Protein: Large, complex treatment, for example fatigue
molecules required for the or nausea.
structure, function and regulation
of the body’s tissue and organs.
36 www.myeloma.org.uk
Genetics Infoguide Feb 2017 Barrs Final.indd 36 14/03/2017 12:31:26Smouldering myeloma: The Thalidomide: A type of
term used to describe an early immunomodulatory drug which
stage of myeloma in which there is given orally.
is paraprotein in the blood but Velcade® (bortezomib): A type of
no symptoms and no damage to proteasome inhibitor drug which
organs. Smouldering myeloma is given either by intravenous
patients do not require treatment. infusion or subcutaneous
Stem cells: A type of cell from injection.
which a variety of cells develop. White blood cells: A type of
Haematopoietic stem cells give blood cell involved in the body’s
rise to red blood cells, white immune system, which help to
blood cells and platelets. They fight infection and disease.
are harvested and collected for
stem cell transplantation.
Infoline: 0800 980 3332 37
Genetics Infoguide Feb 2017 Barrs Final.indd 37 14/03/2017 12:31:26Further information
and useful organisations
United Kingdom
Anthony Nolan www.anthonynolan.org
0303 303 0303
Anthony Nolan is a charity that matches individuals willing to donate
their bone marrow or blood stem cells to people who need lifesaving
transplants. It also provides information and support for patients and
families who are going through a bone marrow or stem cell transplant.
Bloodwisewww.bloodwise.org.uk
02080 888
Bloodwise funds research into leukaemia and related blood disorders
including lymphoma and myeloma. It also provides free patient
information booklets on blood cancers and the related disorders.
Blue Badge Scheme www.gov.uk
England: 0343 100 1000
Northern Ireland: 0300 200 7818
Scotland: 0343 100 1001
Wales: 0343 100 1002
The Blue Badge Scheme provides a national arrangement of on-street
parking concessions enabling people with severe walking difficulties
who travel, either as drivers or passengers, to park close to their
destinations.
38 www.myeloma.org.uk
Genetics Infoguide Feb 2017 Barrs Final.indd 38 14/03/2017 12:31:26British Association for Counselling and Psychotherapy (BACP)
01455 883 300 www.bacp.co.uk
If you are wondering whether counselling is something you should
consider the BACP provide information on what therapies are
available and what they can help with. If you are looking for a therapist
you can search the register on their website.
British Heart Foundation www.bhf.org.uk
0300 330 3311
The British Heart Foundation provides information and support to
people with heart conditions. They fund specialist heart nurses and
run rehabilitation courses around the UK.
British Red Cross www.redcross.org.uk
0344 871 11 11
Volunteers assist with a range of local services – including care in the
home, transport and loans of mobility equipment – to help those with
health issues lead a full and independent life.
Cancer Black Care www.cancerblackcare.org.uk
020 8961 4151
Cancer Black Care provides a comprehensive support service to ALL
members of the community who are affected by cancer, including
advice on what financial support is available and advocacy.
Infoline: 0800 980 3332 39
Genetics Infoguide Feb 2017 Barrs Final.indd 39 14/03/2017 12:31:26Cancer Focus Northern Ireland www.cancerfocusni.org
028 9066 3281
Cancer Focus Northern Ireland’s Living Well services provide one to
one and group support for people with a cancer diagnosis and their
family members. It’s a range of therapies and activities that you can
tailor to meet your needs at each stage in your experience of cancer.
Cancer Research UK www.cancerresearchuk.org
0808 800 4040
Cancer Research UK provides a free information service about cancer
and cancer care for patients and their families.
Carer’s Allowance Unit
0345 608 4321
General information about the carer’s allowance, and assistance with
filling in the application form.
Carers Trust www.carers.org
0300 772 9600
The Carers Trust works to improve support, services and recognition
for anyone living with the challenges of caring, unpaid, for a family
member or friend who is ill, frail, disabled or has mental health or
addiction problems. They also provide support specifically for young
carers.
40 www.myeloma.org.uk
Genetics Infoguide Feb 2017 Barrs Final.indd 40 14/03/2017 12:31:26Carers UK www.carersuk.org
0808 808 7777
Carers UK provides advice, information and support for carers. It
produces a directory of national and local carer organisations and can
show you where to get help in your area.
Citizens Advice Bureau (CAB) www.citizensadvice.org.uk
England: 03444 111 444 Wales: 03444 77 20 20
Northern Ireland: call your local Bureau Scotland: 0808 800 9060
Citizens Advice Bureau offers advice about debt and consumer
issues, benefits, housing, legal matters and employment. It provides
assistance with claiming welfare benefits, including practical help
with filling out benefit application forms. Check your local telephone
directory for details of your nearest branch.
Cruse Bereavement Care www.cruse.org.uk
0808 808 1677
Cruse Bereavement Care exists to promote the wellbeing of bereaved
people and to enable anyone bereaved to understand their grief
and cope with their loss. The organisation provides face-to-face and
telephone support, counselling and information.
Disability Rights UK www.disabilityrightsuk.org
Disability Rights UK produce high quality information, products and
services developed by and for disabled people. They also supply keys
for the National Key Scheme (NKS) which offers disabled people
independent access to locked public toilets around the UK.
Infoline: 0800 980 3332 41
Genetics Infoguide Feb 2017 Barrs Final.indd 41 14/03/2017 12:31:26electronic Medicines Compendium (eMC) www.medicines.org.uk
The eMC contains up to date, easily accessible information about
medicines licensed for use in the UK. It includes a Medicine Guides
section which has been developed to help you understand your
medicines and to take them safely.
Gov.UK www. gov.uk
A government website which provides information about a wide range
of public services including benefits such as Attendance Allowance,
Personal Independence Payments and Carer’s Allowance. You will
find phone numbers listed to discuss the different benefits that are
available.
Help with Health Costs www.nhs.uk/Healthcosts
0300 330 1343
Help with Health Costs gives information about prescription charges
and getting help with health costs, such as travelling to appointments,
in England and Wales.
Hospice UK www.hospiceuk.org
020 7520 8200 (Monday – Friday, 9am – 5pm)
Hospice UK supports the development of hospice care in the UK.
They have a register of hospices on their website that you can search
to find one near you.
42 www.myeloma.org.uk
Genetics Infoguide Feb 2017 Barrs Final.indd 42 14/03/2017 12:31:26Institute for Complementary and Natural Medicine (ICNM)
0207 922 7980 www.icnm.org.uk
The ICNM keeps a register of complementary therapy practitioners,
which you can search on their website to find one near you.
Leukaemia CARE www.leukaemiacare.org.uk
08088 010 444 (24 hours a day, 7 days a week)
Leukaemia CARE exists to provide care and support to all those
whose lives have been affected by blood cancers like leukaemia,
lymphoma and myeloma.
Macmillan Cancer Support www.macmillan.org.uk
0808 808 0000
Provides practical, medical and financial information and support to all
cancer patients and their carers. If you are deaf or hard of hearing you
can use the textphone service on 0808 808 0121.
Marie Curie Cancer Care www.mariecurie.org.uk
0800 090 2309
Marie Curie provides specialist palliative nurses to care for people
in their own homes and also has Marie Curie Centres providing free
respite and hospice care throughout the UK. Your District Nurse can
arrange for a Marie Curie nurse to support you.
Infoline: 0800 980 3332 43
Genetics Infoguide Feb 2017 Barrs Final.indd 43 14/03/2017 12:31:26MedicAlert®www.medicalert.org.uk
01908 951 045
MedicAlert is a non-profit charity that provides ID bracelets, necklaces
and watches help make sure that you receive fast, relevant treatment
in an emergency.
Mindwww.mind.org.uk
0300 123 3393
Mind is a charity which provides advice and support to empower
anyone experiencing mental health problems. Their Infoline can
provide information on a range of topics relating to mental health.
National Debtline www.nationaldebtline.org
0808 808 4000
Offers free, confidential and independent advice on how to deal with
debt problems in England, Wales or Scotland.
National Institute for Health and Care Excellence www.nice.org.uk
0300 323 0140
NICE is an independent organisation responsible for providing
guidance on promoting good health and preventing and treating ill
health in England. NICE produces guidance on health technologies
(the use of new and existing medicines, treatments and procedures)
and clinical practice (guidance on the appropriate treatment and care
of people with specific diseases) within the NHS.
44 www.myeloma.org.uk
Genetics Infoguide Feb 2017 Barrs Final.indd 44 14/03/2017 12:31:26National Kidney Federation www.kidney.org.uk
0845 6010 209
The National Kidney Federation provides information about kidney
disease and dialysis, and promotes best practice in renal medicine.
NHS Blood and Transplant www.blood.co.uk
0300 123 23 23
Provides patient information on blood transfusions, including the
benefits and risks of the procedure.
NHS 111 Service www.nhs.uk/111
NHS 111 is staffed by a team of fully trained advisors, supported by
experienced nurses and paramedics. You can call 111 when you need
medical advice fast but it’s not a 999 emergency. NHS 111 is available
24 hours a day, 365 days a year. Calls are free from landlines and
mobiles.
NHS Choices www.nhs.uk
NHS Choices is the UK’s biggest health website. It provides a
comprehensive health information service from the National Health
Service on conditions, treatments, local services in England and
healthy living.
OvercomeDepressionwww.overcomedepression.co.uk
OvercomeDepression aims to offer a unique reference point for
information and practical advice on depression.
Infoline: 0800 980 3332 45
Genetics Infoguide Feb 2017 Barrs Final.indd 45 14/03/2017 12:31:26Pain Association Scotland www.painassociation.com
0800 783 6059
Pain Association Scotland offers support to people with chronic pain
and organises pain management support groups across Scotland.
Pain Concern www.painconcern.org.uk
0300 123 0789
Pain Concern provides a range of information about self-help
and managing pain. Its helpline offers information, support and
a listening ear.
Patient Advice Liaison Services (PALS)
These are available in England to provide patients and their families
with information regarding health related enquiries, NHS services and
other support available. They can provide information about the NHS
complaints procedure and how to get independent help if you decide
you may want to make a complaint. You will be able to find your local
service through your hospital, or by searching on the NHS Choices
website www.nhs.uk.
Penny Brohn Cancer Care www.pennybrohncancercare.org
(formerly Bristol Cancer Help Centre)
0303 3000 118
Based in Bristol, Penny Brohn Cancer Care offers specialist support
including complementary therapies, nutritional advice and counselling for
people affected by cancer. Its helpline provides emotional support and
information about complementary therapists and services in your area.
46 www.myeloma.org.uk
Genetics Infoguide Feb 2017 Barrs Final.indd 46 14/03/2017 12:31:26You can also read
