At the other end of this spectrum, detection of the myeloid protein is due to a hematological malignancy, i.e. multiple myeloma, Waldenström macroglobulinemia, or other B cell-associated neoplasm, that has developed, often in a stepwise manner, from their MGUS precursors.
They contribute to immunity by making antibodies that bind with and thereby initiate the process of neutralizing specific antigens that usually are found on the surface of invading pathogens and foreign substances.
Antibodies are classified as IgG, IgA, IgE, IgD, and IgM based on their being made up of γ, α, ε, δ, or μ heavy chains, respectively.
In consequence of these "primary genomic changes", an expanding clone of cells develops; overproduces and secretes a monoclonal IgM, IgG, IgA, IgE, or IgD antibody, a κ or λ light chain, an α, γ, or μ heavy chain, or, very rarely, fragments of these proteins; and may accumulate "secondary genomic changes" that cause them to become malignant.
Genes affected include those regulating genome stability itself (e.g. KIF2B[12]) as well as cellular activation, proliferation, and apoptosis (e.g. CIDEC,[13] TP52, ATM, KRAS, NRAS, Wnt, and NF-κB).
The condition is typically discovered as an incidental finding when serum protein electrophoresis is done for various reasons unrelated to plasma cell dyscrasias.
[6] In a more recent study, MGUS patients that had the presence of none, 1, 2, or 3 of the three following risk factors, serum M protein levels >15 gram/liter, a non-IgG isotype, and abnormal free light chain ratios, had 5, 32, 37, and 58% chances, respectively, of progressing to multiple myeloma within 20 years.
Studies indicate that both plasma cells and lymphoblastic cells infiltrate involved tissues and that one or perhaps both cell types harbor mutations in a) the MYD88 gene (~20% in IgM MGUS and >90% in IgM-related malignancies), almost all of which are L265P mutations (i.e. changing leucine to proline at the 265th amino acid position of the MYK88 protein thereby causing the protein to be continuously active in stimulating the same cell-activating pathways that Toll-like receptors activate intermittently and on a physiologically basis); b) the CXCR4 gene (8% in IgM MGUS, 25% in IgM-related malignancies); and c) increased gene copy number due to chromosomal rearrangements (36% in IgM MGUS, 82% in IgM-related malignancies).
[17] In all events, IgM MGUS is diagnosed in individuals who have serum IgM levels less than 30 gram/liter; have less than 10% of nucleated bone marrow cells with the lymphoplasmacytic morphology, and have no symptoms or findings of end organ dysfunction attributed to Waldenström macroglobulinemia such as anemia, decreases in any white blood cell count, cold agglutinin disease, hyperviscosity of blood, lymphadenopathy, hepatomegaly, splenomegaly, peripheral neuropathy, cryoglobulinemia, or constitutional symptoms.
A second long-term study of 116 individuals with IgM MGUS found a 15-fold increased risk of progressing to a lymphoid malignancy, mostly to Waldenstorm's macroglobulinemia.
[17] Individuals diagnosed with light chain MGUS typically do not express detectable levels of an IgG, IgA, IgD, IgE, or IgM intact myeloma protein in their blood.
Increased excretion of a urinary monoclonal light chain (typically >0.5 gram/day), which suggests the presence of a particularly severe form of kidney injury (myeloma cast nephropathy), supports but is not a requirement for the diagnosis of MGRS.
Regardless of the exact pathophysiology causing monoclonal immunoglobulin-induced kidney injury, MGRS has a greater morbidity and mortality than other forms of MGUS.
During a 15-year follow-up, the Clinic subsequently reported that patients progressed to Waldenström macroglobulinemia, amyloidosis, or a related IgM-associated neoplasm at a rate of 6%, 39%, 59%, and 68% after the first, third, fifth, and tenth year, respectively.
However, the Southwest Oncology Group in a study on 231 individuals reported that the smoldering disease progressed to overt Waldenström macroglobulinemia over 9 years in only 26% of cases.
These deposits disrupt tissue architecture and, in the case of light chains, directly injure cells, thereby causing potentially cataclysmic organ failures.
Typically, patients developing this type of amyloidosis have had excess κ or λ free light chains in their urine for years before diagnosis.
[25] Diagnosis of the disease requires evidence of increased levels of a κ or λ myeloma protein in blood and/or blood, presence of an amyloid-related organ-involvement syndrome, detection in tissues of amyloid deposition based on birefringence-staining with Congo red, and detection in tissues of κ or λ deposition based on electron microscopy or mass spectrometry.
[26] The disease often presents late in its course with signs and/or symptoms of kidney failure such as those associated with the nephrotic syndrome and is therefore treated as a malignant condition.
The syndrome is defined by the presence of; both of two major criteria, peripheral neuropathy and a clonal plasma cell dyscrasia (increased bone marrow plasma cells in ~67% of cases; ≥1 plasmacytoma in ~33% of cases); at least one other major criteria (Castleman's disease, sclerotic bone lesions, elevated serum levels of the cytokine VEGF); and at least one minor criterion (organomegaly, extravascular volume overload [e.g. ascites, edema, pleural effusion, and/or pericardial effusion], endocrinopathy [i.e. hypogonadism, defects in the hypothalamic–pituitary–adrenal axis], skin changes, papilledema, and/or hematological manifestations [i.e. thrombocytosis or polycythemia]).
[32] Patients suffering type 1 cryoglobulinemia present with symptoms due to cold temperature-induce blood hyperviscosity and consequential interruptions of blood flow, e.g. skin lesions (lower extremity purpuric spots and papules, acrocyanosis, necrosis skin ulcers, livedo reticularis urticaria), peripheral neuropathy, blurred vision, loss of vision, hearing loss, headaches, confusion, transient ischemic attacks, chest pain, heart failure, glomerulonephritis, kidney failure, oral bleeding, and nasal bleeding.
Symptomatic patients typically exhibit levels of a myeloma protein >5 gram/liter and can be diagnosed by simple observing the temperature-induced, reversible induction of serum precipitate formation.
Patients, particularly those with catastrophic presentations, are treated with plasma exchange and/or plasmapharesis to reduce the load of circulating myeloma proteins and relieve acute symptoms.
Solitary plasmacytoma is an early stage malignancy with a clinical course that lies between MGUS and multiple myeloma in the spectrum of plasma cell dyscrasias.
[33] Its diagnoses must meet all four of the following criteria: biopsy-proven tumor consisting of clonal plasma cells; no evidence of any other plasmacytomas based on bone survey and MRI (or in place of MRI, CT scan); normal bone marrow examination; and absence end organ damage, CRAB features, or other signs or symptoms of systemic disease attributable to a plasma cell dyscrasia.
While a pre-malignant phase is likely, most new cases of non-secretory multiple myeloma are brought to attention not because of incidental M protein detection which by definition is absent but because of patient symptoms indicative of malignancy possibly of plasma cell origin.
[36] A Mayo Clinic study of 124 patients initially diagnosed as having non-secretory multiple myeloma were later found to be composed of 65% free light chain secretors and 35% true non-secretors.
[43] Patients with primary plasma cell leukemia present with clinical findings that are less commonly found in multiple myeloma, e.g. they often have hepatomegaly, splenomegaly, lymphadenopathy, nerve and central nervous system defects, bleeding tendencies secondary to thrombocytopenia, and pleural effusions.
Patients resistant to antibiotic trials have been treated with multiple drug chemotherapy to obtain complete remission rates of 64% and an overall 5 year survival of 67%.
Regardless of presentation pattern, these patients may have an aggressive or indolent disease with courses ranging from the asymptomatic presence of a stable monoclonal heavy chain in the serum or urine (e.g. MGUS) to a rapid, downhill progression of a few weeks' duration.