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:
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)
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.
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)
Diagnosis – ALL of the following
Diagnosis – ANY of the following
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)
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:
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).
These are technically classified as multiple myeloma due to the above criteria, even though they may be asymptomatic
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.
Features seen in active multiple myeloma include: (3)
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).
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).
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).
Thickened blood caused by the excess of proteins in the blood
"CRAB" can be used to help remember the common signs and symptoms of Multiple Myeloma (2).
1 or more of the following abnormalities are usually seen (1,3)
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)
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.
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)
Patients are grouped into either high risk, intermediate risk or standard risk based on the FISH evaluation.(2)
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)
This stage is dependent on hemoglobin, serum calcium, imaging of bones on X-ray, and level of the M-protein in blood or urine.
Determined by serum creatinine level
Substage A = Cr <180 mmol/L
Substage B = Cr >180 mmol/L
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)
All patients receive induction chemotherapy. After induction chemotherapy, treatment options include further chemotherapy, autologous HCT, or clinical trial treatments.(1)
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 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 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))