Multiple myeloma is a cancer of plasma cells, a type of white blood cell normally responsible for producing antibodies. Initially, often no symptoms are noticed.
When advanced, bone pain, bleeding, frequent infections, and anemia may occur. Complications may include amyloidosis. Multiple myeloma is considered treatable but generally incurable.
With current treatments, survival is usually 4–5 years.
Because many organs can be affected by myeloma, the symptoms and signs vary greatly.
A mnemonic sometimes used to remember some of the common symptoms of multiple myeloma is CRAB:
C = Calcium (elevated)
R = Renal failure,
A = Anemia
B = Bone lesions.
Myeloma has many other possible symptoms, including opportunistic infections (e.g., pneumonia) and weight loss. CRAB symptoms and proliferation of monoclonal plasma cells in the bone marrow are part of the diagnostic criteria of multiple myeloma.
The most common site of bone lesions in vertebrae. Credit: Blausen Medical Communications, Inc., CC BY 3.0
Bone pain affects almost 70% of patients and is the most common symptom. Myeloma bone pain usually involves the spine and ribs, and worsens with activity. Persistent localized pain may indicate a pathological bone fracture.
Involvement of the vertebrae may lead to spinal cord compression or kyphosis. Myeloma bone disease is due to the overexpression of receptor activator for nuclear factor κ B ligand (RANKL) by bone marrow stroma. RANKL activates osteoclasts, which resorb bone.
The resultant bone lesions are lytic (cause breakdown) in nature and are best seen in plain radiographs, which may show “punched-out” resorptive lesions (including the “raindrop” appearance of the skull on radiography). The breakdown of bone also leads to the release of calcium into the blood, leading to hypercalcemia and its associated symptoms.
The anemia found in myeloma is usually normocytic and normochromic. It results from the replacement of normal bone marrow by infiltrating tumor cells and inhibition of normal red blood cell production (hematopoiesis) by cytokines.
The most common cause of kidney failure in multiple myeloma is due to proteins secreted by the malignant cells. Myeloma cells produce monoclonal proteins of varying types, most commonly immunoglobulins (antibodies) and free light chains, resulting in abnormally high levels of these proteins in the blood.
Depending on the size of these proteins, they may be excreted through the kidneys. Kidneys can be damaged by the tubulopathic effects of proteins or light chains.
Increased bone resorption leads to hypercalcemia and causes nephrocalcinosis, thereby contributing to the kidney failure. Amyloidosis is a distant third in the causation. Patients with amyloidosis have high levels of amyloid protein that can be excreted through the kidneys and cause damage to the kidneys and other organs.
Light chains produce myriad effects which can manifest as the Fanconi syndrome (type II renal tubular acidosis). Other causes include hyperuricemia, recurrent infections (pyelonephritis), local infiltration of tumor cells, and drug induced.
The most common infections are pneumonias and pyelonephritis. Common pneumonia pathogens include S. pneumoniae, S. aureus, and K. pneumoniae, while common pathogens causing pyelonephritis include E. coli and other Gram-negative organisms.
The greatest risk period for the occurrence of infection is in the initial few months after the start of chemotherapy. The increased risk of infection is due to immune deficiency.
Although the total immunoglobulin level is typically elevated in multiple myeloma, the majority of the antibodies are ineffective monoclonal antibodies from the clonal plasma cell. A selected group of patients with documented hypogammaglobulinemia may benefit from replacement immunoglobulin therapy to reduce the risk of infection.
Some symptoms (e.g., weakness, confusion, and fatigue) may be due to anemia or hypercalcemia. Headache, visual changes and retinopathy may be the result of hyperviscosity of the blood depending on the properties of the paraprotein.
Finally, radicular pain, loss of bowel or bladder control (due to involvement of spinal cord leading to cord compression) or carpal tunnel syndrome, and other neuropathies (due to infiltration of peripheral nerves by amyloid) may occur. It may give rise to paraplegia in late-presenting cases.
When the disease is well-controlled, neurological symptoms may result from current treatments, some of which may cause peripheral neuropathy, manifesting itself as numbness or pain in the hands, feet, and lower legs.
Multiple Myeloma Risk Factors
Monoclonal gammopathy of undetermined significance (MGUS) increases the risk of developing multiple myeloma. MGUS transforms to multiple myeloma at the rate of 1% to 2% per year, and almost all cases of multiple myeloma are preceded by MGUS.
Obesity is related to multiple myeloma with each increase of body mass index by 5 increasing the risk by 11%.
A familial predisposition to myeloma exists. Hyperphosphorylation of a number of proteins – the paratarg proteins – a tendency which is inherited in an autosomal dominant manner appears a common mechanism in these families. This tendency is more common in African American patients with myeloma and may contribute to the higher rates of myeloma in this group.
Top Image: Nephron, CC BY-SA 3.0. Micrograph of a plasmacytoma.Multiple myeloma (which is diagnosed using several clinical criteria) is, histologically, a plasmacytoma.