The following module was designed to supplement medical students’ learning in the clinic. Please take the time to read through each section by clicking the headings below. Information on anatomy, pathophysiology, epidemiology, etiology and risk factors, classification, presentation, investigation, diagnosis, staging, treatment and prognosis of multiple myeloma is provided.

By the end of the tutorial, the following objectives should be addressed:

1. Understand the general development of plasma cells and the general anatomy of an immunoglobulin.
2. Understand that multiple myeloma arises from MGUS.
3. Describe the terminology used for multiple myeloma cells and the proteins they form.
4. Describe the current prevalence of multiple myeloma.
5. Identify the risk factors associated with multiple myeloma.
6. Understand the various classifications for multiple myeloma, including monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM).
7. Define the general types of plasmacytomas.
8. Understand the major differences in diagnosis between MGUS, SMM and multiple myeloma.
9. Understand the general approach to treatment of MGUS and SMM.
10. Describe the common presentation of a patient with multiple myeloma.
11. Understand the common results seen in a patient with multiple myeloma.
12. Describe the common investigations used to diagnose multiple myeloma.
13. Understand the general approach to diagnosing multiple myeloma.
14. Understand the tests used for pre-treatment evaluations of multiple myeloma patients.
15. Describe the major systems used for multiple myeloma staging.
16. Identify the common methods of treatment for each stage of melanoma.
17. Describe how the different modalities of chemotherapy, radiation and surgery are used to treat multiple myeloma.
18. Understand the relationship between the type of disease and the treatment.
19. Describe the factors related to the prognosis of an individual with multiple myeloma.

Multiple myeloma is a malignant proliferation of plasma cells. Plasma cells are a type of white blood cell that makes antibodies/immunoglobulins. The majority of plasma cells are found in the bone marrow, but they also exist in tissues and organs. (1)

Immunoglobulins have both heavy and light chains. There are 5 types of immunoglobulins – IgG, IgA, IgM, IgD, and IgE. They are named after the structure of their heavy chains. (1)

Multiple myeloma is a malignancy of late-stage B cells. It occurs when a mutation of a single clone of a plasma cell (a monoclonal plasma cell) occurs and results in the propagation and increased production of immunoglobulins. These cells are sometimes called myeloma cells. Myeloma cells can accumulate and form tumours called plasmacytomas within or outside the bone. They also form monoclonal immunoglobulins called an M-protein or paraprotein. This protein does not serve any useful function. Instead, it causes problems such as anemia, kidney dysfunction, and increased blood viscosity. See more in Presentation. (1,2)

The most common immunoglobulins produced by myeloma cells are IgG or IgA.  IgD and IgE are rare. Sometimes the myeloma cells release free light chains instead of immunoglobulins. These free light chains are called Bence-Jones proteins. This protein can be excreted and detected in the urine. (1)

When there is proliferation of plasma cells without end organ damage, a patient is said to have Monoclonal Gammopathy of Unknown Significance (MGUS). This is common and can be seen in up to 5% of the general population over age 70. When this proliferation of plasma cells expand to the point of end-organ dysfunction, it is referred to as Multiple Myeloma. A type of Multiple Myeloma called Smouldering Multiple Myeloma is an asymptomatic intermediate stage between MGUS and active multiple myeloma. See more in Classification. (1)

Multiple Myeloma is the most common plasma cell cancer and is more common in the elderly. It accounts for about 1.2% of new cancer diagnoses each year (1). It is responsible for about 10% of all hematologic malignancies. Deaths from multiple myeloma compromise about 20% of deaths from hematologic malignancies and 2% of all cancer deaths.

MGUS occurs in over 3% of the population over 50 years old. There is a 1% yearly risk of progressing to myeloma or another related malignancy. (2)

Unfortunately the etiology of multiple myeloma is not well understood. Most of the cases arise from MGUS (monoclonal gammopathy of undetermined significance).

The most commonly accepted mechanism of how MGUS arises is that antigenic stimulation causes an abnormal plasma cell response, leading to cytogenetic abnormalities. It has also been proposed that genetic abnormalities and the environment of the bone marrow may play a role in the development of MGUS. (1)

The risk factors for developing MGUS and thus Multiple Myeloma are as follows.(1, 2)

Monoclonal Gammopathy of undetermined significance (MGUS)

MGUS is a precancerous condition that may lead to multiple myeloma. It is asymptomatic and has no significant clinical findings. The minority of MGUS progress to multiple myeloma (at about 1% risk per year). MGUS can also lead to amyloidosis, macroglobulinemia, or other lymphoproliferative disorders.

• Features seen in MGUS are
• M-protein level in the blood at less than 30g/L (this is often quite stable for many years) AND
• Plasma cell levels less than 10% of the blood cells in the bone marrow AND
• No tumors AND
• No CRAB features (hypercalcemia, Renal dysfunction, Anemia, Bone disease)

MGUS may be classified further in terms of the risk of progression to Multiple Myeloma. Treatment includes testing to rule out other diagnoses, as well as watchful waiting. Each visit should include a physical exam and a blood and urine test to monitor for M-protein levels. (1)

Low Risk MGUS

Diagnosis – ALL of the following

• M-protein level less than 15g/L
• IgG type M-protein
• Normal free light chain ratio
• 2% risk of developing Multiple Myeloma or related condition at 20 years
• Followup SPEP in 6 to 12 months. If results are normal, retest every 2 to 3 years or earlier if symptoms arise

High Risk MGUS

Diagnosis – ANY of the following

• M-protein level more than 15g/L
• IgA or IgM type M-protein
• Abnormal free light chain ratio

If 3 of above features, 58% risk of developing Multiple Myeloma or related condition at 20 years

If 2 of above features, 37% risk of developing Multiple Myeloma or related condition at 20 years

If 1 of above features, 21% risk of developing Multiple Myeloma or related condition at 20 years

Patients usually have a follow-up bone marrow aspiration and biopsy. Patients with IgM MGUS may have a CT scan to look for enlarged lymph nodes (signs of other conditions)

• Followup SPEP and CBC every 6 to 12 months, or earlier if symptoms arise. 

Smouldering Multiple Myeloma (also known as Indolent Multiple Myeloma)

Smouldering Multiple Myeloma (SMM) is a condition that lies on the spectrum between MGUS and active multiple myeloma. Unlike MGUS, SMM has a larger M-protein or a higher percentage of plasma cells in the bone marrow. Unlike multiple myeloma, there is no end-organ damage. SMM is asymptomatic. Most patients with this condition will go on to develop active multiple myeloma (2).

Features seen in Smouldering multiple myeloma include:

• Plasma cells taking up 10 to 60% of the blood cells in the bone marrow
• The M-protein level at 30g/L or more
• Should NOT have: end-organ damage (lytic lesions, anemia, renal disease, hypercalcemia), free light chain ratio of 100 or more, MRI with more than one >5mm focal lesions involving bone or bone marrow

To determine risk, healthcare providers classify smouldering myeloma into the following risk groups. Most these patients are managed conservatively. Very high risk patients can be treated as if they had active multiple myeloma (2).

Low Risk SMM

• Plasma cells make up less than 10% of the blood cells in the bone marrow AND the M-protein level is 30g/L or more
• These patients usually progress to multiple myeloma in 19 years or more

Intermediate Risk SMM

• Plasma cells make up 10% or more of the blood cells in the bone marrow AND the M-protein level is less than 30g/L
• These patients usually progress to multiple myeloma in about 9 years

High Risk SMM

• Plasma cells make up 10% or more of the blood cells in the bone marrow AND the M-protein level is 30g/L or more
• These patients usually progress to multiple myeloma in about 2.5 years

Very High Risk SMM

These are technically classified as multiple myeloma due to the above criteria, even though they may be asymptomatic

• Plasma cells make up 60% or more of the blood cells in the bone marrow AND the serum free light chain ratio is 100 or more AND an MRI scan shows more than one area of bone or bone marrow destruction
• These patients are treated as if they have stage 1 multiple myeloma.

SMM is usually closely followed up and no treatment should be initiated. If there are doubts as to whether or not a patient should initiate treatment, a reassessment should be done in 2 to 3 months (2).

Labwork should be done including SPEP (serum protein electrophoresis), CBC, Cr, UPEP (urine protein electrophoresis), immunofixation, FLC ratio (free light chain ratio), and bone marrow biopsy. For more explanation on these investigations, please see the section on Investigations.

Imaging should include skeletal survey and one of CT, MRI or PET of whole body or spine and pelvis.

Repeat SPEP, CBC, Cr, Ca, FLC ratio, UPEP and urine immunofixation in 2-3 months. If the results are stable, repeat testing every 4-6 months for 1 year, then every 6-12 months.

Imaging can be repeated with a metastatic bone survey every year and repeat MRI initially every 3-6 months. 

Active Multiple Myeloma (Symptomatic Multiple Myeloma)

Features seen in active multiple myeloma include: (3)

• M-protein in the blood or urine
• Plasma cells that make up 10% or more of the blood cells in the bone marrow
• A plasmacytoma in the bone or soft tissue
• Anemia, kidney failure, hypercalcemia
• Osteolytic lesions 

Solitary plasmacytoma of the bone

This is a single tumour made of myeloma cells with no other features of multiple myeloma. Plasma cells make up less than 10% of all the cells in the bone marrow. Symptoms may include bone pain at tumour site. Treatment is often done with radiation therapy. About 1/3 of these patients will go on to develop multiple myeloma (5). 

Extramedullary plasmacytoma

Tumour made up of myeloma cells starting outside of the bone marrow. Common sites include upper respiratory tract, paranasal sinuses, nasal cavity and larynx. (6).

This diagnosis is made after biopsy of the lesion. These patients usually have normal X-rays and bone marrow biopsies. A MRI or PET may be warranted to check other areas of the body. (6).

Treatment includes radiation therapy or surgery (6).

Light Chain Myeloma

The myeloma cells in this condition do not make a full immunoglobulin but instead release free light chains. Light chains can accumulate in the kidneys and damage kidney function. Since the light chains are smaller than M-proteins, they are able to be filtered into the kidneys into the urine. In the urine, they are known as Bence-Jones proteins. 15-20% of people with multiple myeloma have light chain myeloma. (4). 

Bone symptoms

• "Bone pain” in the back or chest at time of diagnosis, usually worse with movement and not significant at night.
• Radiculopathy – caused by fractures of vertebrae, leading to increased pressure on the nerve roots. Often occurs in chest, lower back or legs. Common neurologic symptoms are numbness or tingling, pain, or muscle weakness
• Symptoms of spinal cord compression (caused by plasma cells growing into spinal canal) = Severe back pain, muscle weakness, numbness or tingling, paralysis, confusion, dizziness, bowel or bladder dysfunction
• Pathological fractures due to the bone loss throughout the body – the most common are vertebral fractures. This also decreases height. (1.2)

Symptoms of hypercalcemia

• Nausea, vomiting, abdominal pain, anorexia, frequent urination, increased thirst, constipation, weakness, drowsiness, confusion, stupor, or coma (1.2)

Hematologic symptoms

• Symptoms of anemia – pallor, weakness, fatigue, dyspnea, lightheadedness
• Increased infection susceptibility/increased number of infections or fever
• Symptoms of thrombocytopenia – epistaxis, bleeding gums, bruising etc.(1,2)

Symptoms of hyperviscosity syndrome 

Thickened blood caused by the excess of proteins in the blood

• Bleeding from nose and mouth, blurred vision, neurologic symptoms, heart failure, headaches, dizziness, weakness, drowsiness, fatigue, thickened blood from cuts, bruising, stroke-like symptoms (1,2)

Other Symptoms

• Weight loss
• Large purple coloured lesions below skin (tumor cells accumulating beneath skin)
• Kidney dysfunction symptoms – weakness, shortness of breath, itching, swelling (1,2) 

“CRAB” 

"CRAB" can be used to help remember the common signs and symptoms of Multiple Myeloma (2).

• hyperCalcemia
• Renal insufficiency
• Anemia
• Bone symptoms

Lab Tests 

1 or more of the following abnormalities are usually seen (1,3)

• Hypercalcemia – this is due to the breakdown of bone, which releases calcium into the bloodstream. The peptide PTHrP, parathyroid hormone related peptide, is generated in multiple myeloma and acts similar to parathyroid hormone, causing increased bone resorption and renal retention of calcium.
• Anemia – this occurs is 2/3 of patients with multiple myeloma and is caused by the decreased number of red blood cells, due accumulation of plasma cells in the bone marrow
• Impaired kidney function – often seen at diagnosis. This is due to the excess proteins and hypercalcemia causing damage to the kidneys 

Tests that can show abnormalities include those listed below. For tests to be done post-diagnosis for a pre-treatment evaluation, see section on Diagnosis. (1,3)

• CBC (This can show anemia, thrombocytopenia and changes in the white cell count that can signify underlying infection or immunocompromised states)
• Increased BUN and Cr (This can show kidney dysfunction)
• Increased serum Ca (This is due to increased activity of osteoclasts)
• Other lab values including: Increased uric acid, increased LDH, decreased albumin, decreased beta-2-microglobulin
• Quantitative Ig
• Protein electrophoresis – 70% of multiple myeloma patients have high IgG, 20% have high IgA and 5-10% have immunoglobulin light chains (Bence-Jones proteins)

1. SPEP (serum protein electrophoresis) to look for M-proteins in the blood
2. UPEP (urine protein electrophoresis) or 24 hr protein to look for M-proteins in the urine
3. Immunofixation = a technique used to determine which type of immunoglobulin was identified on SPEP or UPEP
4. Serum Free Light Chain Assay = This assay is done if the electrophoresis does not show a monoclonal protein and suspicion for MM is high). It quantifies serum free light chains and can detect ratio of serum free light chains (kappa and lambda light chains are usually found in a 1:1 ratio in the body, but this ratio is abnormal in those with MM)

• Urinalysis - Can detect amount of Bence-Jones protein
• Genetic or chromosomal testing may be done to evaluate possible response to treatment and survival.(1,3)

Imaging

• Skeletal Survey (X-ray) – can be used to check for lytic lesions, bone erosion or look for plasmacytoma. Views of the chest, entire spine, humeri and femora, skull and pelvis are evaluated, as well as any symptomatic areas. Lytic lesions and areas of bone erosion are seen in 80% of patients at time of diagnosis. The most commonly affected areas are the vertebrae, ribs, pelvic bones, femurs and humeri.  If the X-rays are inconclusive, but the patient continues to have symptoms suggestive of MM, other imaging such as CT, MRI or PET may be done.
• CT/MRI/PET – can be used to look for changes in bone marrow, broken or weakened bones, or plasmacytoma. An MRI or PET is needed for ruling out other lesions before diagnosing plasmacytoma in a patient. An MRI can be used to check for spinal cord compression. (1,3)

Other Investigations

Bone Marrow Aspiration and Biopsy – tissue collected will be analyzed histologically and can also be sent for cytogenetic testing (including karyotyping and fluorescence in situ hybridization/FISH), immunohistochemistry and flow cytometry. Bone marrow aspiration and biopsy may show an abnormally high percentage of bone marrow cells (>10%). Different areas of bone marrow may vary in how affected they are by MM.(1,3)

For Diagnosis for MGUS and SMM, please see Classification.

Diagnosis of multiple myeloma requires the following:

One of: 

• Bone marrow aspirate or biopsy showing at least 10% plasma cells OR 
• Presence of a plastocytoma (plasma cell tumor) 

PLUS

One of:

• Evidence of damage to the body due to plasma cell growth (severe bone damage, kidney failure, anemia, hypercalcemia) with the cutoffs for anemia, hypercalcemia and renal insufficiency are <100 g/L, >2.75 mmol/L, and <40 mL/min respectively OR 
• Detection of at least 60% plasma cells in the bone marrow OR 
• Detection of a free light chain ratio of 100 or more OR MRI showing more than 1 lesion involving bone or bone marrow.

It is important to diagnose this accurately – often MGUS or SMM patients may be diagnosed incorrectly (for example, if they have renal failure due to another cause and mistakenly are diagnosed with renal failure due to plasma cell disorder.) If one is uncertain about the diagnosis, a reasonable approach is to follow-up with the patient in 2 months’ time. (1,2)

Once diagnosis has been established, a pre-treatment evaluation should be done, which should include: (1,2)

• CBC and peripheral smear
• Chemistry, including serum Ca, albumin, LDH, beta-2-microglobulin, and CRP
• Creatinine and eGFR
• Serum free monoclonal light chain measurement
• SPEP (serum protein electrophoresis) with immunofixation and quantitation of immunoglobulins
• Routine urinalysis and 24 hour urine electrophoresis (UPEP) and immunofixation
• Bone marrow aspiration and biopsy with immunophenotyping, cytogenetics, and fluorescence in situ hybridization (FISH). FISH probes should include t(11;14), t(4;14), t(6;14), t(14;16), t(14;20), trisomies of odd numbered chromosomes, 1q+, and del17p13.
• Metastatic bone survey with X rays of humerus and femoral bones or low dose whole body CT
• Additional MRI or PET/CT if neurological deficits or spinal cord compression is suspected 

Risk stratification

Patients are grouped into either high risk, intermediate risk or standard risk based on the FISH evaluation.(2) 

High-risk myeloma (15%) – median survival 2-3 years with standard treatment

• t(14;16), t(14;20), or del17p13 by FISH
• LDH levels ≥2 times the upper limit of normal
• Features of primary plasma cell leukemia (defined by either ≥2000 plasma cells/microL of peripheral blood or ≥20 percent on a manual differential count)
• High-risk signature on gene expression profiling

Intermediate-risk myeloma 

• t(4;14) or gain (1q) by FISH, OR deletion 13/hypodiploidy by conventional cytogenetics

Standard-risk myeloma – median survival 8-10 years

• Anyone else who does not fit the above categories. This includes patients with trisomies, t(11;14), and t(6;14)

Patients should be assessed as to whether or not they are eligible for future autologous hematopoietic cell transplantation (HCT). HCT can prolong survival compared to chemotherapy alone. Some factors that may play a role are age and functional status.(2)

There are two staging systems for staging Multiple Myeloma. (1) 

Durie and Salmon Staging System

This stage is dependent on hemoglobin, serum calcium, imaging of bones on X-ray, and level of the M-protein in blood or urine. 

Substages of Durie-Salmon Staging

Determined by serum creatinine level

Substage A = Cr <180 mmol/L

Substage B = Cr >180 mmol/L

‍

International Staging System

 This stage is dependent on albumin and beta-2-microglobulin. 

For the most part, patients with monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) do not require therapy. High risk SMM may sometimes be treated like early stage Multiple Myeloma. See the section on SMM under Classification for more details.

Multiple Myeloma is generally not curable. Treatment is given to symptomatic patients or high risk patients. Additional treatment, including chemotherapy, is dependent on patient age, functional status and the availability of an autologous stem cell donor. Lack of treatment is associated with mortality in an average of 6 months post diagnosis.

The first step is to determine whether a patient is eligible for hematopoietic stem cell transplant. Eligibility criteria varies, but is often based on age and functional status. (1,2,3)

Chemotherapy:

All patients receive induction chemotherapy. After induction chemotherapy, treatment options include further chemotherapy, autologous HCT, or clinical trial treatments.(1)

Radiation:

Solitary plasmacytoma may be cured (as opposed to systemic myeloma). Radiation therapy is the main treatment for any solitary plasmacytoma of the bone or extramedullary plasmacytoma. Radiation can also help prevent fractures and control symptoms such as bone pain in those with myeloma, as a palliative measure.(1)

Surgery:

Surgery can be used occasionally such as in cases of spinal cord compression, to treat bone fractures, or to resect extramedullary plasmacytoma. This is usually done post-radiation therapy.(1)

Treatment Response:

Treatment response can be evaluated by measuring the monoclonal protein in serum or protein or by measuring the free light chain assay.

Often, patients may relapse and require further therapy. Treatment for relapsed disease is indicated if there is clinical relapse (symptoms) or a rapid rise in monoclonal protein.

Complications include hypercalcemia, renal insufficiency, infection, skeletal lesions, and infections.

Supportive therapy includes using corticosteroids to lessen chemotherapy side effects, bisphosphonates to prevent further bone destruction, antibiotics to treat infection, and plasmapheresis to help remove M-protein from the blood.  Pneumonoccocal and influenza vaccines should be given to prevent infection. (1,2,3)

There are several factors that can also attribute to the potential aggressiveness of multiple myeloma in a patient. (1,2))

Anatomy

1. Multiple Myeloma. (2017). www.cancer.ca. Retrieved 26 July 2017, from http://www.cancer.ca/en/cancer-information/cancer-type/multiple-myeloma/multiple-myeloma

Pathophysiology

1. Multiple Myeloma. (2017). www.cancer.ca. Retrieved 26 July 2017, from http://www.cancer.ca/en/cancer-information/cancer-type/multiple-myeloma/multiple-myeloma
2. Rajkumar, S. (2017). Pathobiology of multiple myeloma. Uptodate.com. Retrieved 26 July 2017, from https://www.uptodate.com/contents/pathobiology-of-multiple-myeloma

Epidemiology

1. Canadian Cancer Statistics 2017. (2017). Canadian Cancer Society. Retrieved 26 July 2017, from http://cancer.ca/Canadian-CancerStatistics-2017-EN.pdf
2. Rajkumar, S. (2017). Clinical course and management of monoclonal gammopathy of undetermined significance. Uptodate.com. Retrieved 27 July 2017, from http://www.uptodate.com/contents/clinical-course-and-management-of-monoclonal-gammopathy-of-undetermined-significance

Etiology and Risk Factors

1. Multiple Myeloma. (2017). www.cancer.ca. Retrieved 26 July 2017, from http://www.cancer.ca/en/cancer-information/cancer-type/multiple-myeloma/multiple-myeloma
2. Rajkumar, S. (2017). Diagnosis of monoclonal gammopathy of undetermined significance. Uptodate.com. Retrieved 26 July 2017, from https://www.uptodate.com/contents/diagnosis-of-monoclonal-gammopathy-of-undetermined-significance

Classification

1. Rajkumar, S. (2017). Diagnosis of monoclonal gammopathy of undetermined significance. Uptodate.com. Retrieved 26 July 2017, from https://www.uptodate.com/contents/diagnosis-of-monoclonal-gammopathy-of-undetermined-significance
2. Rajkumar, S. (2017). Smoldering multiple myeloma. Uptodate.com. Retrieved 26 July 2017, from https://www.uptodate.com/contents/smoldering-multiple-myeloma
3. Rajkumar, S. (2017). Clinical features, laboratory manifestations, and diagnosis of multiple myeloma. Uptodate.com. Retrieved 26 July 2017, from https://www.uptodate.com/contents/clinical-features-laboratory-manifestations-and-diagnosis-of-multiple-myeloma
4. Multiple Myeloma. (2017). www.cancer.ca. Retrieved 26 July 2017, from http://www.cancer.ca/en/cancer-information/cancer-type/multiple-myeloma/multiple-myeloma
5. Rajkumar, S. (2017). Diagnosis and management of solitary plasmacytoma of bone. Uptodate.com. Retrieved 26 July 2017, from http://www.uptodate.com/contents/diagnosis-and-management-of-solitary-plasmacytoma-of-bone
6. Rajkumar, S. (2017). Diagnosis and management of solitary extramedullary plasmacytoma. Uptodate.com Retrieved 26 July 2017, from https://www.uptodate.com/contents/diagnosis-and-management-of-solitary-extramedullary-plasmacytoma

Presentation

1. Multiple Myeloma. (2017). www.cancer.ca. Retrieved 26 July 2017, from http://www.cancer.ca/en/cancer-information/cancer-type/multiple-myeloma/multiple-myeloma
2. Rajkumar, S. (2017). Clinical features, laboratory manifestations, and diagnosis of multiple myeloma. Uptodate.com. Retrieved 26 July 2017, from https://www.uptodate.com/contents/clinical-features-laboratory-manifestations-and-diagnosis-of-multiple-myeloma

Investigations

1. Multiple Myeloma. (2017). www.cancer.ca. Retrieved 26 July 2017, from http://www.cancer.ca/en/cancer-information/cancer-type/multiple-myeloma/multiple-myeloma
2. Brigden, M. (2014). Monoclonal gammopathy and primary care. British Columbia Medical Journal, 56(1), 14-22. 
3. Rajkumar, S. (2017). Clinical features, laboratory manifestations, and diagnosis of multiple myeloma. Uptodate.com. Retrieved 26 July 2017, from https://www.uptodate.com/contents/clinical-features-laboratory-manifestations-and-diagnosis-of-multiple-myeloma

Diagnosis

1. Multiple Myeloma. (2017). www.cancer.ca. Retrieved 26 July 2017, from http://www.cancer.ca/en/cancer-information/cancer-type/multiple-myeloma/multiple-myeloma
2. Rajkumar, S. (2017). Clinical features, laboratory manifestations, and diagnosis of multiple myeloma. Uptodate.com. Retrieved 26 July 2017, from https://www.uptodate.com/contents/clinical-features-laboratory-manifestations-and-diagnosis-of-multiple-myeloma

Staging

1. Multiple Myeloma. (2017). www.cancer.ca. Retrieved 26 July 2017, from http://www.cancer.ca/en/cancer-information/cancer-type/multiple-myeloma/multiple-myeloma

Treatment

1. Multiple Myeloma. (2017). www.cancer.ca. Retrieved 26 July 2017, from http://www.cancer.ca/en/cancer-information/cancer-type/multiple-myeloma/multiple-myeloma
2. Brenner, T., Duggal, S., Natale, J., & Wirth, S. (2017). Treatment protocols for multiple myeloma. Uptodate.com. Retrieved 26 July 2017, from https://www.uptodate.com/contents/treatment-protocols-for-multiple-myeloma
3. Rajkumar, S. (2017). Overview of the management of multiple myeloma. Uptodate.com. Retrieved 26 July 2017, from https://www.uptodate.com/contents/overview-of-the-management-of-multiple-myeloma

Prognosis

1. Multiple Myeloma. (2017). www.cancer.ca. Retrieved 26 July 2017, from http://www.cancer.ca/en/cancer-information/cancer-type/multiple-myeloma/multiple-myeloma
2. Rajkumar, S. (2017). Staging and prognostic studies in multiple myeloma. Uptodate.com. Retrieved 26 July 2017, from https://www.uptodate.com/contents/staging-and-prognostic-studies-in-multiple-myeloma