QuestionSBA
QuestionChoice
Osteoarthritis presents with chronic joint pain made worse on activity. There are no associated blood abnormalities or increased risk of fractures, and so this diagnosis does not, therefore, explain the clinical presentation.
53240
d
Osteoarthritis
QuestionChoice
This patient has renal impairment, anaemia, hypercalcaemia, and evidence of fractures. These characteristics make myeloma the most likely diagnosis. Myeloma is a haematological malignancy caused by the clonal proliferation of plasma cells which secrete monoclonal antibodies. Myeloma investigation requires a combination of serum immunoglobulins, serum protein electrophoresis, and serum free light chains, to identify a monoclonal gammopathy with isotype suppression. Serum free light chains function in lieu of urinary Bence Jones proteins, which are liable to false negative results if not processed rapidly. The ALP is normal in multiple myeloma.
53237
a
Multiple myeloma
QuestionChoice
Light chain amyloidosis is a potential complication of multiple myeloma. Amyloidosis can cause dysfunction in virtually any organ due to widespread deposition of the proteins. This patient may well have amyloidosis secondary to his multiple myeloma, but this does not represent the underlying diagnosis, and so the better answer is multiple myeloma. Histology of fat biopsies (taken from samples of the rectum or abdomen) typically shows apple green birefringence with congo red stain under polarised light.
53241
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Amyloid light chain amyloidosis
QuestionChoice
Waldenstrom's macroglobulinaemia is a lymphoplasmacytic lymphoma (non-Hodgkin) where there is excess production of IgM paraprotein. The clinical features of myeloma are absent, such as hypercalcaemia, bone lesions (which are characteristically lytic), anaemia, and kidney disease, and the patient presents with hyperviscosity syndrome instead (such as bleeding gums, blurred vision, headache, confusion.) Since this is a lymphoma, lymphadenopathy and hepatosplenomegaly may be present. These features are not present in this case.
53238
b
Waldenstrom's macroglobulinemia
QuestionChoice
Paget's disease is usually found incidentally on a blood test with an isolated raised ALP. It clinically presents with bone pain and pathological fractures. This question stem eludes to the use of a back brace secondary to a recent compression fracture. Although this is expected for myeloma and Paget's, you would expect to see bony deformities in Paget's disease (such as frontal bossing), as well as a raised ALP.
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Paget's disease
QuestionComment
give reference ranges.
28916
User
subscriber
Bartholin Cyst
QuestionComment
why is every answer multiple myeloma
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subscriber
Kawasaki Body 
Concept
Chapter
# Summary 

Multiple myeloma is a malignant plasma cell dyscrasia characterized by the proliferation of abnormal plasma cells in the bone marrow. These plasma cells secrete monoclonal antibodies (most commonly of the Ig subtype) and antibody fragments into the serum and the urine. There is also a relative deficiency of functional antibodies, resulting in a relative hypogammaglobulinaemia. This condition leads to bone destruction, kidney dysfunction, anaemia, and a range of systemic symptoms. Multiple myeloma primarily affects older adults and is associated with genetic and environmental factors. The management of multiple myeloma involves a combination of chemotherapy, immunomodulatory drugs, and stem cell transplantation, aiming to control the disease, alleviate symptoms, and improve overall survival.

# Definition

Multiple myeloma is a **plasma cell dyscrasia** characterised by abnormal clonal proliferation of post-germinal B cells (plasma cells)


# Epidemiology

Multiple myeloma is the second most common haematologic malignancy, accounting for approximately 1% of all cancers. It predominantly affects older adults, with the median age at diagnosis around 69 years, and those of Afro-Caribbean descent are affected twice as frequently as Caucasians, and men more than women.

# Aetiology

The development of multiple myeloma is multifactorial. It is associated with several risk factors, including genetic predisposition, exposure to radiation or certain chemicals, and immunosuppressive conditions.




# Signs and Symptoms

The clinical features of multiple myeloma can be remembered by the mnemonic CRAB HAI:

- Hyper**C**alcaemia – arises primarily owing to increased osteoclast-mediated bone resorption. Results in: moans (painful bones), stones (renal stones), groans (GI symptoms) and psychiatric moans (neurological effects  such aslethargy, fatigue, memory loss, psychosis, depression)
- **R**enal impairment – occurs because of multiple factors (eg. light chain deposition in the kidneys and hypercalcaemia)
- **A**naemia – other cytopenias (eg. thrombocytopenia and leukopenia) can also occur due to marrow infiltration by the tumour 
- **B**one pathology – **Back pain** is very common. Osteolytic lesions are common, which can lead to pathological fractures and vertebral compression fractures
- **H**yperviscosity – can present with headache, visual disturbance and thrombosis
- **A**myloidosis (AL subtype) – can have multiple sequelae including cardiac failure and neuropathy
- **I**nfection – recurrent infection occurs secondary to leukopenia and immunoparesis (ie. low levels of functional IgG)

# Differential Diagnosis

* **Monoclonal Gammopathy of Undetermined Significance (MGUS):** MGUS is a precursor condition to multiple myeloma, characterized by the presence of M-proteins. It is typically asymptomatic and does not meet the criteria for myeloma.
* **Waldenström Macroglobulinaemia:** This condition, like myeloma, involves the overproduction of immunoglobulins, but it predominantly affects B cells and presents with hyperviscosity syndrome and lymphoplasmacytic lymphoma.
* **Amyloidosis:** Amyloidosis can manifest with similar symptoms, including renal dysfunction, but it results from the deposition of abnormal protein fibers (amyloids) rather than the proliferation of plasma cells.

# Investigations

Investigations can be classified into those that form part of the initial work-up, diagnostic tests and investigations to inform prognosis.

- Work-up investigations

  - **FBC** – may show anaemia
  - **U&E** – may show renal impairment (particularly raised serum creatinine) and/or hypercalcaemia (with normal ALP), which is a common feature
  - Raised ESR (the positive charge of the protein neutralises the negative charge of the sialic acid on the red cell membrane, reducing the red cells natural tendency to repulse each other, so they fall down the column faster)
  - **Skeletal survey** – typically done with X-rays, but CT/MRI are more sensitive
    - Findings include osteolytic bone lesions and pathological fractures

- Diagnostic investigations

  - **Serum and/or urine electrophoresis** – This will show a paraprotein spike (typically IgG)
  - **Serum free light chain** assay (Bence Jones protein)	
  		- Can be kappa or lambda 
    	- Serum-free light chain levels are high in myeloma
   	 - can be  a useful test in the 1–2% of patients with nonsecretory multiple myeloma (ie. those who do not have a serum/urine monoclonal protein on electrophoresis)

  - Tissue diagnosis typically by **bone marrow** aspirate and biopsy 
    - Myeloma is confirmed if there are >10% plasma cells in the bone marrow


# Management 

Myeloma can present as an acute emergency: 

- Acute renal failure – swift treatment of volume depletion is critical, as well as early involvement of renal physicians 
- Hypercalcaemia – fluid and bisphosphonates needed
- Hyperviscosity – requires plasmapheresis
- Spinal cord compression – should be treated as a radiotherapy emergency

Specific treatment for myeloma depends on the presence of poor prognostic factors and comorbidities – there is no complete cure for myeloma but treatments attempt to induce remission.

- **Conservative management**
  - An option for patients with minimal symptoms and no end-organ damage
  - Patients will require regular follow-up, with consideration of initiation of therapy when/if signs of active disease appear

- **Haematopoietic stem cell transplantation**

  - A treatment option for younger patients who have minimal comorbidities – most haematologists will consider this option up to the age of 70 years
  - The patient will require **induction therapy** with a nonchemotherapeutic (eg. bortezomib, thalidomide and dexamethasone) (VTD) given together with Daratumumab (monoclonal antibody binding CD38) (DVTD). The standard upfront trajectory for myeloma is DVTD  then Autograft then DVTD consolidation then Lenalidomide maintenance.
  
    - Non-chemotherapeutic options are replacing chemotherapeutic options as they have a lower toxicity rate.

  - A **conditioning regimen** (high-dose melphalan) followed by **autologous stem cell transplant** is the preferred option

  - Autologous transplants have a low transplant mortality rate (<1%), but also a lower remission rate (40%) than allogeneic transplants

  - Allogeneic transplants have a higher transplant mortality rate but also a higher remission rate


- **Patients unsuitable for stem cell transplantation**
  - The standard of care for such patients is melphalan, prednisolone and thalidomide (MPT)
    - This induces good event-free survival
  - Lenalidomide (antiangiogenic) is an alternative to thalidomide
  - Most patients will relapse after initial treatment
    - Further combination therapies of thalidomide, melphalan, lenalidomide, bortezomib (proteasome inhibitor) or dexamethasone can be used such as VMP.


- **Supportive management**

Patients should be monitored regularly, with the frequency of monitoring depending on how aggressive their disease is.

# Complications

* **Bone Disease:** Multiple myeloma often leads to bone destruction, pathological fractures, and skeletal-related events. Treatment includes bisphosphonates and denosumab to strengthen bones.
* **Renal Dysfunction:** Kidney impairment is a common complication, requiring close monitoring and potential interventions.
* **Infections:** Patients with myeloma are at increased risk of infections due to weakened immune function. Preventative measures and prompt treatment are essential. Influenza and pneumococcal vaccination should be given for infection prevention.
* **Anaemia:** Should be managed with erythropoietin (± transfusion) for anaemia

# Prognosis

The prognosis in multiple myeloma is influenced by various factors that help assess the overall outlook and guide treatment decisions. One significant prognostic tool is the International Staging System (ISS), which stratifies patients into three stages based on the levels of two serum markers: beta-2 microglobulin and albumin.

- Investigations to inform prognosis include:

  - **β2 microglobulin** (a very high or very low level confers poor prognosis)
	    - Used in the staging of myeloma by the International Staging System (ISS), which relates to β2 microglobulin and albumin levels
  - **LDH** (the higher the level, the worse the prognosis)
  - CRP (the higher the level, the worse the prognosis)
  - FISH and cytogenetic analysis – This may also inform the type of treatment used

**Note**: High serum creatinine and low albumin are also poor prognostic markers.

- Median survival for myeloma is 50% at 5 years.
- High ISS is associated with poor prognosis.

# NICE Guidelines

[NICE CKS - Multiple Myeloma](https://cks.nice.org.uk/topics/multiple-myeloma/)
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A lytic lesion secondary to multiple myeloma.
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The typical appearance of multiple myeloma.
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Myeloma
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Haematology
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Multiple myeloma
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Cancer
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Multiple myeloma is characterised by renal impairment, anaemia, hypercalcaemia, and bone fractures due to clonal plasma cell proliferation.
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Fatigue
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Cancer
A 61-year-old male under investigation for a 6 month history of fatigue returns to his GP for follow up results of his blood tests.  On examination, he is wearing a back brace as he has sustained a recent vertebral fracture. His blood test results show: 


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|--------------|:-------:|---------------|
|Haemoglobin|97 g/L|(M) 130 - 170, (F) 115 - 155|
|White Cell Count|2.1 x10<sup>9</sup>/L|3.0 - 10.0|
|Sodium|140 mmol/L|135 - 145|
|Potassium|4.1 mmol/L|3.5 - 5.3|
|Urea|7.9 mmol/L|2.5 - 7.8|
|Calcium|3.1 mmol/L|2.2 - 2.6|
|eGFR|49 mL/min/1.73m<sup>2</sup>|> 60|

Liver function tests are normal.


Which of the following is the most likely underlying diagnosis?
a