Myeloma is a cancer that forms from a type of white blood cell called B-cells. Because myeloma usually affects several bone marrow sites in the body, it is also known as multiple myeloma.
In 2016, there were around 130,000 myeloma cases, and the condition was responsible for 98,437 deaths globally.
The exact cause of myeloma is unknown, but scientists believe the cancer may be the result of defects in DNA that lead to the abnormal proliferation of B-cells. These cells, called myeloma cells, accumulate in the bone marrow, where they crowd out the formation of other blood cells such as red blood cells, platelets, and normal white blood cells. This leads to anemia, fatigue, increased bleeding and bruising, and a higher risk of infections. Myeloma cells also promote the breakdown of bones, leading to bone pain and fractures.
B-cells typically produce antibodies against harmful invaders such as viruses, bacteria, and fungi to prevent or fight off an infection. Myeloma cells, however, produce an antibody with no useful function and is known as paraprotein, M-protein, or M-spike. This antibody targets the kidneys instead of foreign invaders, causing kidney damage and potential kidney failure.
Myeloma is genetically heterogeneous so it is difficult to determine the specific mutations that are commonly involved in this cancer’s development. In general, cancer is caused by a combination of mutations in tumor suppressor and oncogenes. Oncogenes are genes involved in cell division and growth. Specific mutations in these genes can favor higher-than-normal cell division.
In a normal cell, the activity of oncogenes is tightly regulated by tumor suppressor genes to prevent uncontrolled cell multiplication. When oncogenes and tumor suppressor genes are mutated within the same cell, cancer such as myeloma can develop.
Myeloma cells are particularly prone to mutations based on their development. During their development, B-cells undergo genetic rearrangements to build a wide selection of different antibodies. The rearrangement process requires DNA breaks and fusion, and these breaks can fuse with other breaks in the genome, leading to chromosomal translocations. Some translocations may involve oncogenes, and thereby give cells a growth advantage. This is one possible cancer trigger in a subset of myeloma cases.
Symptoms of myeloma may vary between patients, but common symptoms include:
- bone pain
- bone fragility
- muscle weakness
- increased bleeding and bruising
- recurring infections
- kidney damage
- frequent urination
- loss of appetite
- excessive thirst
The diagnostic process when myeloma is suspected usually includes a clinical assessment, laboratory tests, kidney function tests, and radiographic imaging.
The clinical assessment consists of an analysis of the patient’s medical and family history, and a physical examination.
Laboratory tests include:
- complete blood cell count
- measurement of paraprotein in the blood and urine
- measurement of hemoglobin levels in the blood
- bone marrow aspirate or bone marrow biopsy to quantify B-cells in the bone marrow
- measurement of blood calcium levels: high calcium levels are a sign of bone destruction, as calcium is released from the bones.
Kidney function tests
Kidney function tests involve:
- measuring the levels of creatinine concentration in the blood. Creatinine is a bioproduct of muscle metabolism, and is excreted by the kidneys. High levels in the blood may be an indicator of kidney dysfunction.
- determining the glomerular filtration rate, the rate at which the kidney removes excess waste and fluid from the body.
When kidney failure is detected, further tests are necessary to determine whether this is caused by myeloma.
A kidney biopsy can detect typical changes in cell appearance associated with myeloma.
Another possibility to identify myeloma as a cause of kidney dysfunction is a measurement of free light chain (FLC) levels. Immunoglobulin light chains are part of antibodies. Free means that the light chains are in an unbound state in the blood. The two different kinds of light chains are kappa and lambda. An unusual ratio of kappa to lambda FLC can be an indicator of myeloma.
The International Myeloma Working Group updated its diagnostic criteria in 2014, and these criteria are the most widely accepted for the diagnosis of myeloma. According to these criteria, myeloma is diagnosed when more than 10% of the cells in the bone marrow are clonal or neoplastic B-cells in the presence of at least one myeloma defining event:
- evidence of end-organ damage that can be attributed to an underlying B-cell disorder
- hypercalcemia: blood calcium levels of more than 3.0 mmol per L
- kidney insufficiency: creatinine clearance lower than 40 ml per minute or serum creatinine levels more than 277 umol per L
- anemia: hemoglobin value lower than 100g per L
- bone lesions
- presence of one or more malignancy biomarkers:
- clonal bone marrow B-cell percentage of 60% or more
- involved/uninvolved blood FLC ratio of 100 or more
- more than one focal lesion on MRI scans
Myeloma is an incurable disease but treatments can help control it, relieve the symptoms, and prolong lives.
The treatment strategy mainly depends on whether or not the patient is eligible for autologous stem cell transplantation (ASCT). Because the therapy involves high doses of chemotherapy, it is very invasive and only recommended for patients who are in good overall health. Some treatments interfere with ASCT and are only used by transplant-ineligible patients.
Immunomodulatory medications are among the most commonly used therapies for myeloma. They seem to work via multiple mechanisms which include, among others, suppressing the growth of myeloma cells and improving the function of the immune system.
Proteasomes are protein complexes that break down and recycle old proteins. They are especially important in cancer cells, such as myeloma cells, because these cells have a high protein turnover. The inhibition of proteasomes results in a build-up of waste proteins, causing the cells to die.
The combination of a proteasome inhibitor with an immunomodulatory treatment has been found to be an effective approach for patients with newly diagnosed myeloma.
Alkylating agents transfer an alkyl group to certain parts of the DNA molecule. This causes breaks in the DNA, affecting the cells’ ability to multiply.
CD38 inhibitors are a type of therapy that targets a protein called CD38, which is primarily found on the surface of myeloma cells.
Darzalex (daratumumab) is a CD38 inhibitor approved by the U.S. Food and Drug Administration for the treatment of newly diagnosed, relapsed, and/or refractory myeloma patients.
Inhibitors of nuclear export
Cancer cells may evade the activity of tumor suppressors by exporting them out of the nucleus. Inhibitors of nuclear export can stop cancer cells from doing this, therefore ensuring that tumor suppressors remain in the nucleus of the cancer cells to kill them.
Xpovio (selinexor) is a nuclear export inhibitor that blocks the action of a nuclear export protein called exportin.
Autologous stem cell transplantation
Autologous stem cell transplantation involves the use of growth factors to stimulate the release of bone marrow stem cells into the bloodstream. The stem cells are then harvested from the blood and frozen for later use. The patient then receives high-dose chemotherapy to destroy the myeloma cells. Because chemotherapy also kills normal bone marrow cells, the collected stem cells are reinfused back into the patient to repopulate the body.
Other medications that are used for myeloma treatment include the corticosteroids dexamethasone and prednisone, the chemotherapeutic medications cysplatin, etoposide, and doxorubicin, the SLAMF7 antibody Empliciti (elotuzumab), and the histone deacetylase inhibitor Farydak (panobinostat).
Treatment of symptoms
Bisphosphonates are agents that slow down the breakdown of bones. They thereby delay the progression of bone lesions and prevent fractures.
Pain management usually starts with non-opioid analgesics. Non-steroidal anti-inflammatory drugs should be avoided because they increase the risk of kidney failure. Opioid analgesics can be used for severe pain.
Antibiotics and antivirals can help prevent infections. Intravenous immunoglobulins are used in patients with severe recurrent bacterial infections.
Last updated: Nov. 19, 2019
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