Multiple Myeloma (MM) is a haematological malignancy that affects B-cells which over stimulates
production of plasma cells (Dowling, Kelly and Meenaghan, 2016). MM is currently incurable
however, symptoms can be managed, allowing patients to live longer. Thus the main aim with MM
patients is to control disease progression with effective management of symptoms, increasing
quality of life and prolonging survival (Dowling, Kelly and Meenaghan, 2016).
Epidemiological Basis
MM is the 17th most common type of cancer in
the UK in 2016, as shown in figure 1 (Office for
National Statistics, 2018). MM accounted for 2%
of all cancer cases registered in the UK in 2015
(Cancer Research UK, 2018). Although the
definitive cause is uncertain, chromosomal
abnormalities such as deletions can be a factor
(Tewari et al., 2011; Vangsted, Klausen and Vogel,
2011).
The biggest risk factor is age. Majority of patients
are over 60 years old with just 2% under the age
of 40 (Brody, 2011). There is a strong correlation
with myeloma incidence and age, as shown in
figure 2, highest incidence rates are among older
people. This reflects the fact that DNA damage
accumulates over time with the drop in data at
the oldest ages being due to reduced diagnostic
activity (Cancer Research UK, 2018).
Monoclonal Gammopathy of Undetermined
Significance (MGUS) and Smoldering Multiple Myeloma (SMM), asymptomatic versions of MM,
both have strong associations for developing MM (Schey, 2014). MGUS and SMM carry differing
risks to progress to active myeloma (Ramasamy and Lonial, 2015). However, as they are both
asymptotic in presentation, they are detected at
much later stages of the condition.
Predisposition to MM is identified to be MGUS
and SMM with a progression rate of 1% and
10% respectively (Schey, 2014). Several
studies have reported a strong correlation of a
genetic predisposition to those with a family
history of MGUS (Ramasamy and Lonial,
2015). Close relatives have an increased risk
of developing it as they inherit variations in
certain genes that can progress to MM. On
the contrary, certain inherited variations can
also reduce the risk of developing MM
(Genetics Home Reference, 2018).
Another risk factor is gender. MM is less
prevalent in women than in men in reported
cases, with 42% and 58% respectively (Cancer
Research UK, 2018). Figure 2 supports this
association. Incidence seems to increase steeply
in conjunction with age with the gender-specific curves diverging. Patients with autoimmune
diseases or are immunocompromised also present with greater risks to MM (Brody, 2011).
Identifying Patients
Identification of patients with MM can be difficult with the condition only presenting at the later
stages. Paraproteins, which are immunoglobulins produced by the plasma cells, build up in the
bone marrow which begin to weaken bones (Kyle and Rajkumar, 2009; Brody, 2011). In MM, these
paraproteins, which were asymptomatic in MGUS, proliferate and become malignant leading to
the common symptoms such as anaemia, bone lesions and kidney failure (Brody, 2011). Often its
upon diagnosis of these symptoms that lead to the discovery of MM. Other symptoms can
include hypercalcaemia, hyper-viscous blood, repeated infections. The main symptoms are often
referred to as CRAB features, the expanded abbreviation for CRAB is C= elevated calcium, R=
renal failure, A= anaemia, B= bone lesions (Rajkumar, 2011). Common mis-diagnosis include
marking bone pain or fatigue as non-urgent which prolongs detection and treatment (Dowling,
Kelly and Meenaghan, 2016).
The elderly are definitely most at risk, as covered in the epidemiological basis. Often old age also
decreases the efficacy of the immune system in detecting and eradicating malignancies. Older
age demographics also attend fewer diagnostic procedures due to other health restrictions which
impairs early detection.
Pathology Services & Clinical Significance
Investigations for patients suspected with myeloma, according to NICE guidelines, should include
Serum Protein Electrophoresis (SPE) and Serum-free light-chain (sFLC) assays (Nice.org.uk,
2016). These assays detect presence of paraprotein which can indicate MM or MGUS.
Immunofixation should also be requested for abnormal results from SPE. Immunofixation
identifies the exact immunoglobulin present, which can classify the type of myeloma from heavy
chain and light chain disorders. Morphological testing should be used to detect plasma cell
percentage and flow cytometry for plasma cell phenotyping (Nice.org.uk, 2016).
SPE along with Urine Protein Electrophoresis (UPE) can be used to identify amounts of
paraprotein, UPE is not always favoured as urine passed over 24 hours is required (Serum Free
Light Chain Assay, 2007). Profiles produced will be larger than normal, with spikes in the gamma
region indicative of paraprotein production, often called the M spike, shown in figure 5. Greater
the M spike, greater the amount of paraprotein present, as shown in figures 4 and 5 (Serum Free
Light Chain Assay, 2007). SPE results can help determine benign and malignant conditions and so
should be an initial step to diagnosis (Al-hiary et al., 2015). Sensitivity of SPE and UPE is 51% and
35% respectively (Nowrousian, 2005). This shows that SPE is far more specific for the detection
of monoclonal free light chains.
Bone Marrow Aspirate (BMA) and Trephine biopsy should be requested further to the initial testing
to supplement accurate diagnosis (Nice.org.uk, 2016). Fluorescence in-situ Hybridisation (FISH)
assay can provide an accurate prognosis of the exact genetic abnormality present within the
plasma cells from the biopsy. FISH identifies the specific abnormalities significant to myeloma.
Deletion and translations such as t(4;14), t(14;16) and del(17p) have been associated to MM
(Dowling, Kelly and Meenaghan, 2016). Immunophenotyping can also be conducted along with
immmunohistochemistry on the trephine biopsy to provide long-term prognosis and monitoring
(Nice.org.uk, 2016). Recent studies underline the importance for bone marrow trephine biopsy
(BMTB) during follow-up treatment plan. Positive predictive value for both BMA and BMTB were
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Figure 4: Normal SPE profile (Serum Free Light Chain Assay, 2007). Figure 5: Abnormal SPE profile (Serum Free Light Chain Assay, 2007).
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100% with a negative value of 22% and 57% respectively (Joshi et al., 2007). The study
concludes that there was only a significant correlation in BMTB tests and paraprotein levels.
Therefore, the study advocates the use of BMTB along with imunohistochemistry more regularly
even though its not enforced in the current UK guidelines (Joshi et al., 2007).
These results should be used in
conjunction with the biomarker data
for staging according to the
International Staging System (ISS)
scores, shown in table 1, which
highlights high-risk myeloma
patients (Nice.org.uk, 2016; Dowling,
Kelly and Meenaghan, 2016). All
tests that are carried out on bone
marrow should be requested
together to minimise the need for
further samples to be taken from the
patient (Nice.org.uk, 2016).
sFLC assay and sFLC ratio should
also be used to asses prognosis (Nice.org.uk, 2016). sFLC detects free light chains in serum by
using antibodies against epitopes that are ‘hidden’ in intact immunoglobulins (Bhole, Sadler and
Ramasamy, 2014; Tosi et al., 2012). Normal light chain references are: Kappa free light chains 3.3
– 19.4mg per litre of serum and Lambda free light chains 5.71 – 26.3mg per litre of serum (Serum
Free Light Chain Assay, 2007). Reference range for sFLC ratio should be 0.26-1.65 for the light
chains (Bhole, Sadler and Ramasamy, 2014).
sFLC is a more sensitive way to measure the amount of light chains present in blood in
comparison to SPE and UPE (Serum Free Light Chain Assay, 2007). SPE has a lower limit of
500-2000mg/L. It is unable to detect lower concentrations and so, limits the sensitivity (Bhole,
Sadler and Ramasamy, 2014). Therefore, gold standard testing was considered to be UPE
however, its heavily dependant on renal function and threshold (Bhole, Sadler and Ramasamy,
2014). This means its potentially unreliable to diagnosis early stages and advanced stages. Along
with that collection of 24 hours of urine in the correct way and sampling, increases the error
margins (Tosi et al., 2012). sFLC provides accuracy in detecting lower amounts of free light
chains, with a lower detection limit of 0.2mg/L. Being a serum assay also increases the viability by
avoiding the 24 hour urine collection. sFLC also indicates the effectiveness of treatment which
means relapses can be detected
factors such as the chemistry profile, serum beta-2-microglobulin, complete blood count and
immunotyping. As well as a measure of general health and acceptance to treatment, it can
provide basic vital diagnostic data. Chemistry profile and serum beta-2-micorglobulin levels can
be a measure of renal function which is a classic presentation for myeloma and data from this can
be used in staging of myeloma, shown in table 1 (Brody, 2011). A complete blood count will show
proportions of white blood cells, this can show the extend of the condition but more importantly
show signs of anaemia which is a main symptom and a further factor for treatment. Anaemia can
increase chances of infection and or issues with clotting (Brody, 2011). Immunotyping shows the
type of immunoglobulin present which can suggest presence of MM. All the tests mentioned
should not be used independently to reach a conclusion, but used as a whole to provide a
complete diagnostic image.
Multidisciplinary and Interdisciplinary Approach
MM is an incurable malignancy, requires both a multidisciplinary and interdisciplinary treatment
approach. It is critical for patient welfare and overall treatment success that this happens
efficiently. NICE issue guidance on structure and function of multidisciplinary teams (MDTs) for
haematological cancers. NICE advice that all specimens are collected by a central reception and
for laboratories to have specialist haematopathology input for diagnosis (Nice.org.uk, 2016). This
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Table 1: Staging of patients using specific biomarkers and genetic abnormalities that help distinguish
patients at a greater risk of developing MM before end-organ damage occurs (Dowling, Kelly and
Meenaghan, 2016).
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includes having specific protocols for specimen handling and having a combined pathway
between departments across pathology for compilation of integrated reports. Thus providing
diagnosis, treatment plans and rapid resolutions for patients (Nice.org.uk, 2016).
Pathology services are organised into specific departments that carry out certain tests. All testing
on blood is carried out by haematology. Tests on serum and urine are conducted by biochemistry
department. Biopsy samples are processed and examined by the histology department. So within
pathology itself, three separate departments must collate data to provide the full diagnostic
profile. Complex tests, such as the sFLC and genetic phenotyping of MM, which requires special
machines and specifically trained staff will be carried out by external regional labs (Serum Free
Light Chain Assay, 2007). Therefore coordination between in-house and external labs is also
important.
Other departments involved within the hospital itself is imaging. Skeletal radiography can provide
a pictorial diagnosis of the stage of MM and is currently the screening method of choice
(Ramasamy and Lonial, 2015). CT and MRI scans are useful in characterising the bone lesions as
part of CRAB features. These results are often key in MDT meetings to develop treatment plans as
they also provide information on tissue plasmacytomas and extramedullary disease (Ramasamy
and Lonial, 2015).