Before reading this please take a look at our article on plasma proteins and SPEP!
Multiple myeloma is a blood cancer involving the uncontrolled proliferation of plasma cells in the bone marrow. Each plasma cell produces a certain type of antibody. When there is uncontrolled proliferation of plasma cells, this inevitably results in uncontrolled production of a certain kind of antibody in the body, ultimately resulting in a functional deficiency of antibodies. This uncontrolled production of immunoglobulin is referred to as monoclonal gammopathy. The uncontrolled proliferation of plasma cells in the bone marrow also suppresses the production of other cell types in the bone marrow resulting in leukopenia, thrombocytopenia, and anemia.
Who should I suspect multiple myeloma in?
MM can mimic a lot of other diseases and often times we only suspect it because of incidental findings on lab work (like anemia, thrombocytopenia, leukopenia or hypercalcemia) or non-specific symptoms.
Suspect multiple myeloma in elderly patients (> 50) with
- Repeated spontaneous fractures and back pain from the osteoporosis and lytic bone lesions
- Repeated infections from the leukopenia and functional Ig deficiency
- Petechiae from the thrombocytopenia
- Constitutional symptoms (as with any neoplasm)
- Weakness accompanied by low hemoglobin and signs of anemia
- Foamy urine indicating Bence Jones proteinuria (more on this later)
A mnemonic to help remember the key features is CRAB:
- Calcium high
- Renal insufficiency
- Anemia
- Bone lytic lesions or osteoporosis
I suspect MM among other differentials, what is the best initial test?
Ordering CBC, creatinine and serum protein electrophoresis (SPEP) is typically the first step. CBC will determine whether the patient is anemic, thrombocytopenic and/or leukopenic. Creatinine will look for signs of renal injury that results in MM. SPEP will look for something called the M-spike. In healthy persons, SPEP will generally produce a curve that looks like this:
As albumin is the most abundant plasma protein in the body, it’s normal for its peak to be the highest. With the gamma globulins (which include immunoglobulins), while they are also fairly abundant (although less than albumin), we expect its curve to have a broad base, because there are different types of immunoglobulins.
However, in patients with a monoclonal gammopathy, the gamma curve is going to spike (called the M-spike), and have a narrow base, as seen in the second graph. If we see this, we are fairly confident that this is multiple myeloma, but don’t know the specific immunoglobulin that is actually elevated.
The SPEP came back positive, what next?
Once the screening SPEP came back suggestive of multiple myeloma we can add two more tests in addition to consulting hematology:
- Immunofixation
In immunofixation, we use the combination of electrophoresis and specific antigens (which is why it is called an immunoelectrophoresis test) in order to detect specifically which antibody is being produced en masse that is resulting in the M-spike that was seen on the SPEP.
- Serum free light chain assay (Freelite)
Serum free light chain assay (SFLC) can be used to determine the level of free light chains in the blood. The results from this study can be use to determine the baseline serum free light chain ratio. The SFLC is the involved/uninvolved free light chain ratio, where the involved free light chain is the kappa or lambda that is above the normal reference range, and the uninvolved is the one that is at or below the normal range.
Other tests before the bone marrow biopsy
Much of this would be ordered under the responsibility of the hematologist, especially the staging lab work.
- Calcium levels to look for hypercalcemia
- Elevated ESR
- Peripheral blood smear to look for Rouleaux formation
- Elevated total protein
- Paraprotein gap (low albumin, high total protein)
- Staging lab work
- B2-microglobulin for staging
- LDH for staging
- Albumin for staging
- Quantitative immunoglobulins (measurements of the levels of immunoglobulins in the blood)
- Urinalysis to look for kidney damage; 24 hour urinary protein collection
- UPEP with or without urine immunofixation
- Same as a SPEP except we are using the urine and we are looking for Bence Jones proteinuria (free light chains in the urine)
The Gold Standard
Bone marrow biopsy is the gold standard for diagnosis of MM. We can also form cytogenetics (FISH) to determine whether the patient has a high risk cytogenetic profile or not which can guide management.
Imaging
Skeletal x-ray survey is commonly done to look for lytic lesions which are common in MM. Low dose whole body CT can be performed instead of a skeletal survey as it is more sensitive for smaller osteolytic lesions and is much faster than a skeletal survey. However there is a much higher exposure to radiation.
Diagnostic criteria
Diagnostic criteria for MM and the other associated diseases on the spectrum of monoclonal gammopathy are complex and intricate. The best resource for this is the International Myeloma Working Group (IMWG) criteria for the diagnosis of multiple myeloma.
Types of Multiple Myeloma
Common subtypes
- IgG kappa or lambda
- IgA kappa or lambda
Monitored using SPEP, quantiative Ig and routine lab work.
Light chain myeloma (no heavy chain secretion)
In light chain myeloma, the myeloma cells are only secreting light chains and not heavy chains. This form of light chain myeloma is also referred to as Bence-Jones myeloma and when the light chains are found in the urine it is referred to as Bence-Jones proteinuria.
Light chain myeloma is monitored using serum free light chain assays (Freelite), UPEP and routine lab work.
Non-secretory myeloma
In non-secretory myeloma, the malignant plasma cells produce no M-protein (heavy or light) in either the blood or urine. Nevertheless, a bone marrow biopsy would still reveal malignant cells, you just wouldn’t be able to detect the diseases using a SPEP or UPEP.
Non-secretory myeloma is monitored using serum free light chain assay (since many cases of non-secretory myeloma may actually be oligosectory and/or light chain myeloma) and routine lab work.