Multiple Myeloma

Question 1

Multiple myeloma refers to a malignant disorder of … (mature B lymphocytes).

Answer 1

Multiple myeloma refers to a malignant disorder of plasma cells (mature B lymphocytes).

Question 2

… is the second most common haematological malignancy. It is characterised by excess secretion of a monoclonal antibody. We term it a monoclonal antibody, because it is derived from a single clone of plasma cells that have undergone abnormal proliferation.

Answer 2

Multiple myeloma (MM) is the second most common haematological malignancy. It is characterised by excess secretion of a monoclonal antibody. We term it a monoclonal antibody, because it is derived from a single clone of plasma cells that have undergone abnormal proliferation.

Question 3

MM accounts for 60-70 cases per 1,000,000 people each year, although the overall prevalence of the condition is increasing due to the improved survival with newer treatments. Unfortunately, it still accounts for 2% of cancer-related deaths and it is associated with a number of severe complications including spinal cord compression, renal impairment and hypercalcaemia,

Answer 3

MM accounts for 60-70 cases per 1,000,000 people each year, although the overall prevalence of the condition is increasing due to the improved survival with newer treatments. Unfortunately, it still accounts for 2% of cancer-related deaths and it is associated with a number of severe complications including spinal cord compression, renal impairment and hypercalcaemia,

Question 4

severe complications of multiple myeloma

Answer 4

including spinal cord compression, renal impairment and hypercalcaemia

Question 5

The pathophysiology of MM is still poorly understood but there appears to be a two-step model.

Answer 5

Development of MGUS: almost all cases of MM arise from this premalignant plasma cell disorder. Affects 3% of patients > 50 years old. Initial cytogenetic abnormality occurs (inciting event). Thought to be an abnormal plasma cell response to antigen stimulus. Leads to creation of plasma cell clone that secretes a monoclonal antibody. Most will not develop MM.
Progression from MGUS to MM: rate of progression estimated at 1% per year. Further cytogenetic abnormalities and changes to the bone marrow microenvironment occur, which promotes proliferation. Associated with systemic problems due to plasma cell infiltration of bone marrow and excess light chain secretion.

Question 6

Clinical presentations

Answer 6

The clinical presentation of MM is generally related to the infiltration of plasma cells and secretion of monoclonal antibodies.
Patients with MM may have constitutional features of malignancy including weight loss, fatigue, loss of appetite and/or generalised weakness. There are a number of typical clinical presentations that relate to the excess proliferation and infiltration of plasma cells (usually in bone marrow) and the excess secretion of monoclonal antibodies.

Question 7

Presenting clinical features of multiple myeloma

Answer 7

Bone disease: widespread due to clonal proliferation in bone marrow. Seen as lytic lesions on imaging. Can lead to fractures.
Impaired renal function: >50% have raised creatinine at diagnosis. Kidneys affected in multiple ways. Commonly due to light chain nephropathy (tubules blocked by light chain casts).
Anaemia: seen in >90% at some point during disease course. Normal bone marrow destroyed by proliferation of malignant plasma cells. Renal disease may contribute (EPO deficiency).
Hypercalcaemia: MM-induced bone demineralisation. More common in active disease. At high levels (≥ 2.9 mmol/L) should be treated as a medical emergency. See our notes on hypercalcaemia.
Recurrent or persistent bacterial infection: immune dysfunction and hypogammaglobulinaemia due to suppression of normal plasma cell function.

Question 8

CRAB

Answer 8

C - calcium levels high
R - renal impairment
A - anaemia
B - bone disease

Question 9

What condition?

Answer 9

Multiple myeloma

Question 10

MM can present with a myriad of other clinical features, some presenting as medical emergencies. These may include …, fever (<1%), splenomegaly (1%), … (4%) or lymphadenopathy (1%). Neurological involvement can result from hyperviscosity syndromes, spinal cord compression, peripheral neuropathy or radiculopathy.

Answer 10

MM can present with a myriad of other clinical features, some presenting as medical emergencies. These may include paraesthesia, fever (<1%), splenomegaly (1%), hepatomegaly (4%) or lymphadenopathy (1%). Neurological involvement can result from hyperviscosity syndromes, spinal cord compression, peripheral neuropathy or radiculopathy.

Question 11

Hyperviscosity syndrome: may develop with high paraprotein levels (i.e. high IgA or IgG). Typical symptoms include blurred vision, headaches, mucosal bleeding and dyspnoea due to heart failure. Requires urgent…

Answer 11

Hyperviscosity syndrome: may develop with high paraprotein levels (i.e. high IgA or IgG). Typical symptoms include blurred vision, headaches, mucosal bleeding and dyspnoea due to heart failure. Requires urgent plasma exchange.

Question 12

Spinal cord compression: can occur in 5% of patients during course of disease of..

Answer 12

Spinal cord compression: can occur in 5% of patients during course of disease. Highly variable depending on lesion causing compression, location, and rate of development. See our notes on cord compression.

Multiple myeloma

Question 13

Myeloma should be suspected in any patient with typical features, but particularly those over 60 years old with:

Answer 13

Unexplained bone pain (and pathological fractures)
Fatigue
Symptoms of hypercalcaemia: bone pain, abdo pain, constipation, confusion, polyuria
Weight loss
Symptoms of cord compression: back pain, new leg weakness, bladder/bowel dysfunction
Symptoms of hyperviscosity: headache, blurred vision, shortness of breath, mucosal bleeding
Recurrent infections

Question 14

Those over 60 with these symptoms should be screened/suspected for …

Unexplained bone pain (and pathological fractures)
Fatigue
Symptoms of hypercalcaemia: bone pain, abdo pain, constipation, confusion, polyuria
Weight loss
Symptoms of cord compression: back pain, new leg weakness, bladder/bowel dysfunction
Symptoms of hyperviscosity: headache, blurred vision, shortness of breath, mucosal bleeding
Recurrent infections

Answer 14

Multiple myeloma

Question 15

‘Screening’ for myeloma involves looking for …, which are the secretion product of the malignant clones.

Answer 15

‘Screening’ for myeloma involves looking for monoclonal antibodies, which are the secretion product of the malignant clones.

Question 16

When we ‘screen’ for myeloma we are looking for the secretion product of the malignant clone of plasma cells - the monoclonal antibodies. We can do this using… and ….

Answer 16

When we ‘screen’ for myeloma we are looking for the secretion product of the malignant clone of plasma cells - the monoclonal antibodies. We can do this using protein electrophoresis and immunofixation. Electrophoresis tells us whether there is an increased number of antibodies. This is followed by immunofixation, which tells us what type of antibody has increased (i.e. is it a monoclonal antibody). MM is usually the result of IgG, IgA or the accompanying light chain. It rarely occurs with IgM.

Question 17

NOTE: The presence of an … monoclonal antibody suggests another haematological malignancy termed Waldenstrom macroglobulinemia.

Answer 17

NOTE: The presence of an IgM monoclonal antibody suggests another haematological malignancy termed Waldenstrom macroglobulinemia.

Question 18

Protein electrophoresis

Answer 18

This is a quantitative test that separates proteins into different bands using an electric current. The distance individual proteins travel is dependent on their shape, size and electrical charge. Electrophoresis gives us characteristic band patterns including normal, polyclonal and monoclonal.

Question 19

Immunofixation is a qualitative test that ‘fixes’ proteins in place by using antibodies. It is important for the identification of proteins after separation by electrophoresis.

Answer 19

Question 20

Urine electrophoresis and serum free light chains

Answer 20

Protein electrophoresis assumes that all myelomas secrete an intact antibody. In fact, around 20% of myelomas only secrete light chains. To help detect these myelomas we can send off serum free light chains (SFLCs) or urine for electrophoresis.

SFLCs is a newer test that looks at the amount of light chain unbound to heavy chains within the blood. Light chains are secreted in healthy individuals as plasma cells produce more light chains than heavy chains. Therefore, it is the ratio between the light chains kappa and lambda, which is the most important factor. An elevated ratio is suggestive of myeloma and needs further work-up.

Alternatively, a urine electrophoresis can be completed. Light chains within the serum may be filtered by the kidneys into the urine. Monoclonal light chains detected in the urine are known as Bence-Jones proteins. NICE recommend the use of serum protein electrophoresis and SFLCs in the work-up of suspected myeloma. Depending on the centre, urine electrophoresis may still be used in combination with the above two tests or as an alternative to SFLCs.

Question 21

Diagnosis of MM involves identifying a … antibody, … analysis and assessing organ damage.

Answer 21

Diagnosis of MM involves identifying a monoclonal antibody, bone marrow analysis and assessing organ damage.

Question 22

Diagnostic criteria

Diagnosis of MM involves identifying a monoclonal antibody, bone marrow analysis and assessing organ damage.

The work-up and diagnosis of MM is dependent on identification of a monoclonal antibody (sometimes referred to as M protein or paraprotein), analysis of the bone marrow to look for a population of malignant clonal plasma cells and further laboratory tests and imaging to assess for myeloma-related organ damage.

Answer 22

Monoclonal antibody detection: protein electrophoresis & immunoglobulins, SFLCs +/- urine electrophoresis for Bence-Jones protein
Bone marrow infiltration: bone marrow aspirate and trephine with cytogenetics
Myeloma-related organ damage: FBC, U&Es, bone profile, imaging (whole body MRI or low-dose whole body CT if MRI not suitable). Skeletal survey (x-rays) only used if CT/MRI not possible
Staging if confirmed myeloma: beta-2 microglobulin, albumin

Question 23

Treatment in multiple myeloma

Answer 23

MM is an incurable condition, treatments aim to increase periods of disease remission.

Question 24

Myeloma - is it curable?

Answer 24

There are many options for the treatment of myeloma. Management depends on a patients fitness and co-morbidities, disease severity, initial response to treatment, relapse(s) and previous therapy. All patients should be discussed in an MDT specialising in myeloma and have access to psychological services, palliative care and support, specialist nurses and clinical research.

Unfortunately, there is no cure for myeloma. The aim is to induce disease remission and then maintain disease free survival for as long as possible with ongoing monitoring for disease relapse. The four key areas of management include: induction therapy, autologous stem cell transplantation (ASCT), maintenance therapy and managing relapse or refractory disease.

Question 25

Induction therapy - multiple myeloma

Answer 25

Induction therapy: initial treatment option. Aim to induce remission. Usually combination of three drugs. Choice depends on high-risk features, co-morbidities and plan for ASCT. Example is VRd (Velcade - bortezomib / Revlimid - lenalidomide / dexamethasone - steroid)

Question 26

ASCT: if suitable for transplant, provides best option for long period of remission. Stem cells mobilised, harvested and stored following induction. Subsequently given high-dose chemotherapy (e.g. melphalan). Stem cells then re-infused.

Answer 26

ASCT: if suitable for transplant, provides best option for long period of remission. Stem cells mobilised, harvested and stored following induction. Subsequently given high-dose chemotherapy (e.g. melphalan). Stem cells then re-infused.

Question 27

Multiple myeloma - Maintenance: used to maintain disease remission as long as possible. Given post-induction or post-transplant. Choices include bortezomib or lenalidomide. Typically given until progression.

Answer 27

Maintenance: used to maintain disease remission as long as possible. Given post-induction or post-transplant. Choices include bortezomib or lenalidomide. Typically given until progression.

Question 28

Relapse or refractory disease: almost all patients will relapse, even if they respond to treatment. Therapy indicated if a clinical relapse or rapid rise in paraproteins. Choices include ASCT, rechallenge with previous regimen, or new therapy.

Answer 28

Relapse or refractory disease: almost all patients will relapse, even if they respond to treatment. Therapy indicated if a clinical relapse or rapid rise in paraproteins. Choices include ASCT, rechallenge with previous regimen, or new therapy.

Question 29

Myeloma is associated with a number of complications, which require further management.

Myeloma can lead to devastating complications due to its proliferation in bones, affect on the kidneys and neurological involvement. The management of individual complications is beyond the scope of these notes, but use the linked below for further information on these topics (albeit not specifically linked to myeloma).

Answer 29

Myeloma bone disease: Bisphosphonates used for boney pain.
Hypercalcaemia
Cord compression
Renal impairment
Anaemia

Question 30

Multiple myeloma relapse

Answer 30

Patients with myeloma will invariably relapse following treatment. Subsequent relapses are associated with reducing response to treatment. The median survival is highly variable between patients depending on response to treatment, age of onset and cytogenetic abnormalities.

Question 31

Beta-2 microglobulin is often used as a prognostic tool in the International Staging System (ISS) for myeloma. This divides patients into three groups (I, II, III) based on serum beta-2 microglobulin and albumin levels, which predicts the median survival.

Answer 31

Stage I: median survival 62 months
Stage II: median survival 44 months
Stage III: median survival of 29 months

Question 32

Factors associated with a worse prognosis in MM

Answer 32

Other factors associated with a worse prognosis include high plasma cell counts, high levels of monoclonal antibody in blood/urine or development of complications (e.g. diffuse multiple bone lesions, marked anaemia, hypercalcaemia and renal impairment).

Question 33

A 71 year old male is seen on the medical take with lethargy and weight loss. He has been feeling unwell for several months and was recently referred to the renal clinic for renal impairment. He has a background of hypertension, chronic obstructive pulmonary disease and previous lung cancer managed with lobectomy. He still smokes 3-4 cigarettes per day and drinks 2-3 pints every week. He is otherwise independent and lives with his wife. Over the last two years he has been suffering from intermittent low back pain but has otherwise been healthy. On examination he appears clinically dehydrated, there are coarse crackles at the right lung base and his abdomen is soft and non tender. Observations show BP 140/80 mmHg, HR 115 bpm, RR 22, sats 93% RA, temperature 37.9º. The team send off a series of investigations including a myeloma screen

Which of the following investigations form the most appropriate myeloma screen?

A	Bone marrow biopsy
B	Protein electrophoresis and serum free light chains
C	Urine electrophoresis
D	Protein electrophoresis
E	Full blood count

Answer 33

NICE recommend the use of serum protein electrophoresis and serum free light chains (SFLCs) in the work-up of suspected myeloma.

Question 34

A 64 year old female is bought to the emergency department as a trauma call after falling off her bike. An urgent whole body CT is requested, which shows evidence of multiple spinal fractures of varying ages with associated lytic lesions. There is no compromise of the spinal cord and she has full power of both lower limbs. She is referred to the neurosurgeons for further advice.

Which of the following investigations would help determine the aetiology of the lytic lesions?

A	Protein electrophoresis and serum free light chains
B	Prostate specific antigen
C	Blood film
D	CA125
E	Alpha-fetoprotein (AFP)

Answer 34

A

Question 35

A 62 year old male is seen in haematology clinic following diagnosis of a monoclonal antibody on myeloma screening. He has been getting boney pain for the last few months, particularly at the lower spine. He is currently taking paracetamol, ibuprofen and tramadol as recommended by his GP. The haematologist explains he will need a series of further investigations to look for myeloma.

What is the most appropriate investigation to assess for boney disease in myeloma?

A Skeletal survey
B Computed tomography positron emission tomography (CT-PET)
C Clinical examination
D Whole body magnetic resonance imaging (MRI)
E Ventilation perfusion scan (V/Q)

Answer 35

Myeloma bone disease is best assessed with a whole body MRI scan.
The work-up and diagnosis of myeloma is dependent on identification of a monoclonal antibody, bone marrow analysis and investigations for myeloma-related organ damage.

As part of the work-up for organ damage, a whole body MRI is recommended by NICE to assess for evidence of boney disease. If MRI is not possible, or contraindicated, patients should be offered a whole-body low-dose CT scan. A skeletal survey, which involves the use of numerous x-rays of different skeletal regions, is now reserved for patients unable to undergo either MRI or CT.

Question 36

What proportion of patients with myeloma are at risk of cord compression during the course of their illness?

A	1%
B	5%
C	50%
D	90%
E	100%

Answer 36

Spinal cord compression can occur in 5% of patients during course of disease.
The presentation of cord compression is highly variable. It depends on where the lesion is causing compression and the overall rate of development.

Question 37

Which of the following is not an antibody heavy chain?

A	A
B	B
C	D
D	E
E	G

Answer 37

There are five types of heavy chain (A, G, M, D, E) and two types of light chain (Kappa, lambda). Two heavy chains form with two light chains to create the complete antibody.

Question 38

A 65 year old male presents to the GP with lethargy and generalised weakness. He has been suffering from headaches and lower back pain. He has also started to develop recurrent nosebleeds, which has never previously been an issue. On examination there is evidence of hepatosplenomegaly. The GP requests some formal blood tests including a myeloma screen due to significant weight loss. He has evidence of a normocytic anaemia.. Protein electrophoresis confirms the presence of an IgM monoclonal antibody. His calcium and renal function are normal.

What is the most likely diagnosis?

A	Multiple myeloma
B	Monoclonal gammopathy of undetermined significance (MGUS)
C	Smouldering myeloma
D	Amyloidosis
E	Waldenström macroglobulinaemia

Answer 38

E

The presence of hyperviscosity symptoms in association with hepatosplenomegaly and an IgM monoclonal antibody is suggestive of Waldenström macroglobulinaemia.

Question 39

Approximately, what proportion of patients with myeloma will develop anaemia?

A	10%
B	20%
C	50%
D	75%
E	90%

Answer 39

􏰀Anaemia is typically seen in >90% of patients with myeloma at some point during disease course.
Anaemia predominantly develops due to replacement of normal bone marrow with the proliferation of malignant plasma cells. Deficiency of erythropoietin (EPO), which is the enzyme needed for erythropoiesis (red blood cell development), may also contribute to anaemia in the context of myeloma-related renal disease.

Question 40

A 64 year old female is seen on the renal ward with a suspected new diagnosis of myeloma following a new acute kidney injury and hypercalcaemia. She has evidence of an IgA monoclonal antibody on protein electrophoresis and her serum free light chains are elevated with a ratio of 4:1 (kappa:lambda).

Which of the following investigations would provide a definitive diagnosis of myeloma?

A	Full blood count
B	Bone marrow trephine biopsy
C	Whole body magnetic resonance imaging (MRI)
D	Urea and electrolytes
E	Lymph node biopsy

Answer 40

Confirmation of myeloma requires bone marrow trephine biopsy with aspirate and cytogenetics.
This patient already has evidence of a monoclonal antibody on screening and myeloma-related organ damage (acute kidney injury and hypercalcaemia).

Bone marrow biopsy allows identification of a clonal pool of malignant plasma cells. If these abnormal cells make up ≥10% of the bone marrow population the diagnosis of multiple myeloma can be make in the context of myeloma-related organ damage. If there is no evidence of end-organ damage this is termed smouldering or ‘asymptomatic’ myeloma, which is an advanced pre-malignant stage.

Question 41

Which of the following is a prognostic marker in myeloma?

A	Protein electrophoreiss
B	Beta-2-microglobulin
C	Full blood count
D	Blood film
E	Bence-Jones protein

Answer 41

Beta-2 microglobulin is often used as a prognostic tool in the International Staging System (ISS) for myeloma.

Question 42

A 51 year old male is referred to the haematology clinic with suspected myeloma. He was recently see in the acute medical unit with pneumonia. As part of his work-up for anaemia he had a myeloma screen sent that showed evidence of an IgG monoclonal antibody on protein electrophoresis. A CT chest, abdomen, pelvis on admission was unremarkable without any lymphadenopathy or boney lesions. He has been referred to the gastroenterology team to further investigate his anaemia. He is otherwise well and recovered from his pneumonia. Examination is largely unremarkable and a series of blood tests are requested.

Full blood count: Hb 100 (130-165 g/L), WCC 6.3 (4.00-11.00 10^9/L), platelets 250 (150-450 10^9/L)

Urea & electrolytes: Na+ 141 (135-145 mmol/L), K+ 3.9 (3.5-5.5 mmol/L), Urea 7.1 (3.3-6.7 mmol/L), Creatinine 81 (< 90 umol/L)

Bone profile: phosphate 1.21 (0.80-1.40 mmol/L), albumin 45 (35-50 g/L), calcium 2.34 (2.15-2.6 mmol/L)

Liver function tests: ALP 141 (40-145 IU/L), ALT 45 (10-60 IU/L), Bilirubin 12 (4-16 umol/L)

He subsequently undergoes a bone marrow trephine biopsy and aspirate, which shows relatively normal erythropoiesis, a small increase in plasma cells, but no major infiltration or clonal population.

What is the most likely diagnosis?

A	Smouldering myeloma
B	Non-secretory myeloma
C	Multiple myeloma
D	Monoclonal gammopathy of undetermined significance (MGUS)
E	Acute myeloid leukaemia

Answer 42

The presence of a monoclonal antibody but absence of a clonal population of malignant plasma cells on bone marrow biopsy is suggestive of MGUS.

MGUS refers to a pre-malignant disorder where an abnormal clone of plasma cells start to secrete a monoclonal antibody. It is estimated that MGUS effects 3% of patients > 50 years old. MGUS can subsequently progress to myeloma, but this occurs at around 1% per year and depends on further mutations and changes to the bone marrow microenvironment.

In MGUS, there is usually a low concentration of a monoclonal antibody, bone marrow biopsy shows a concentration of clonal plasma cells < 10% and there is no organ damage related to the clonal plasma cells. In this case, the anaemia is likely being driven by another pathology that requires investigation. Not all patients with MGUS will require further investigation including a bone marrow examination and this will depend on their symptoms, blood tests, and monoclonal antibody concentration. All patient with MGUS are seen by the haematology team at least once to decide on need for further investigation and monitoring.