Multiple myeloma (MM) is a cancer originating in the plasma cells, specialized white blood cells found primarily in the bone marrow. These cells normally produce antibodies, or immunoglobulins, which are proteins essential for fighting infection. In MM, cancerous plasma cells multiply uncontrollably and produce a single, non-functional type of immunoglobulin, referred to as a monoclonal protein or M-protein. Myeloma classification is determined by the specific heavy chain immunoglobulin—IgG, IgA, IgD, IgM, or IgE—that the malignant plasma cells produce.
Defining IgA Multiple Myeloma and Prevalence
IgA Multiple Myeloma (IgA MM) is the form of the disease where plasma cells secrete the Immunoglobulin A (IgA) protein. It is the second most common subtype of multiple myeloma, following Immunoglobulin G (IgG) myeloma. While IgG MM accounts for the majority of cases (typically around 57%), IgA MM represents a significant fraction, generally ranging from 15% to 20% of all myeloma diagnoses.
IgA MM is a common clinical entity, distinguishing it from rarer subtypes like IgD, IgM, and IgE myeloma. The specific characteristics of the IgA protein contribute to unique clinical features distinct from the more frequent IgG subtype.
Comparative Prognosis and Overall Aggressiveness
The question of whether IgA MM is more aggressive is complex, blending historical observations with modern treatment outcomes. Historically, IgA myeloma was often considered to carry a less favorable prognosis than IgG myeloma, with some studies showing lower long-term survival rates. This perceived aggressiveness stemmed from a higher incidence of adverse biological features within the IgA subtype.
Aggressiveness is often measured by metrics like overall survival (OS), progression-free survival (PFS), and the presence of high-risk cytogenetic abnormalities. IgA MM has been associated with a greater frequency of intermediate or high-risk genetic lesions, such as gain of 1q21 or deletion of 13q, which contribute to a more challenging disease course. Furthermore, IgA myeloma cells can show a lower frequency of the protein CD56. This loss of cell-to-cell adhesion is hypothesized to increase the likelihood of the disease spreading outside the bone marrow, known as extramedullary presentation.
Despite these biological distinctions, the difference in prognosis between IgA and IgG myeloma has narrowed significantly with the widespread use of newer therapies, such as proteasome inhibitors. While some studies still show a slight disadvantage in overall survival for IgA patients, the clinical outcome is now often comparable when high-risk features are treated appropriately. The impact of the IgA subtype alone on survival is often marginal compared to the influence of specific high-risk cytogenetic findings that span all myeloma subtypes.
Distinct Clinical Manifestations of IgA Subtype
The IgA protein can lead to specific clinical problems unique to this subtype. A notable complication is an increased risk of hyperviscosity syndrome (HVS), a medical emergency caused by the blood becoming too thick. This occurs because the IgA protein tends to circulate as larger structures called dimers or polymers, which significantly increase the blood’s viscosity more readily than the smaller, monomeric IgG protein.
Symptomatic HVS is relatively uncommon in myeloma (2% to 6% of cases), but IgA MM is a frequent cause. The classic presentation of HVS is a triad of mucosal bleeding, visual changes, and neurological symptoms. Mucosal bleeding, such as frequent nosebleeds (epistaxis) or gum bleeding, results from the thickened blood interfering with platelet function.
Visual disturbances, including blurred vision or retinal hemorrhages, occur due to sluggish blood flow in the delicate retinal vessels. Neurological symptoms, ranging from headaches and dizziness to confusion, are caused by decreased cerebral blood flow. Furthermore, IgA myeloma has been associated with a higher tendency for extramedullary plasmacytomas—tumors that form outside of the bone marrow, often in soft tissues.
Treatment Modalities Specific to IgA Myeloma
The initial treatment for IgA myeloma is largely the same as for other common subtypes, typically involving a triplet regimen. These regimens usually include a proteasome inhibitor, an immunomodulatory drug, and a corticosteroid. However, the management of IgA MM must be tailored to address the specific complications associated with its protein type.
The most urgent difference in management is the need to rapidly address hyperviscosity syndrome if present. For patients with symptomatic HVS, the immediate treatment of choice is plasmapheresis, also known as therapeutic plasma exchange (TPE). This procedure involves removing the patient’s blood plasma, which contains the thickened IgA protein, and replacing it with a substitute fluid.
Plasmapheresis offers immediate, short-term relief by quickly lowering the concentration of the pathogenic IgA protein in the blood. While TPE is a supportive measure that does not treat the underlying cancer, it stabilizes the patient and prevents further organ damage, particularly to the eyes and brain, allowing time for the main anti-myeloma chemotherapy to take effect. Long-term control of IgA protein levels is achieved only by continuing systemic therapy to eliminate the cancerous plasma cell clone.