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. The overproduced monoclonal proteins, termed myeloma proteins, commonly circulate in blood, may accumulate in urine, and are the hallmarks of plasma cell dyscrasias including their most malignant forms viz., multiple myeloma, light chain multiple myeloma, and plasma cell leukemia. IgG-secretory, IgA-secretory, and light-chain secretory multiple myeloma represent 52%, 21%, and 16%, respectively, of all multiple myeloma cases; these myelomas are associated with various types of chromosomal aberrancies and mutations. IgD-secretory multiple myeloma occurs in only 1% to 2% of multiple myeloma cases and is commonly associated with somatic mutations in the gene encoding the gV (i.e. variable) region of the monoclonal antibody. IgE-secretory multiple myeloma has been reported in <50 cases as of 2013 and is characteristically associated with translocations between the q arms of chromosome 11 and 14, i.e. t(11;14)(q13;q32) translocations.In other cases, plasma cells and/or lymphoplasmacytoid cells (a type of B cell resembling, and possible precursor to, plasma cells) suffer other kinds of mutations that lead to the production of an IgM myeloma protein. Overproduction of this myeloma protein may progress to a different form of plasma cell/lymphoplasmacytoid cell malignancy, Waldenström macroglobulinaemia.
a Glomerular filtration rate of <40; and c) biopsy confirmed or suspicion of cast nephropathy, glomerulonephritis, of other morphological expressions of clonal immunoglobulin-induced kidney injury. 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. The disorder can also be caused by a monoclonal immunoglobulin that acts as an autoantibody that activates the blood complement system to cause complement-related kidney injury. This form of MGRS is usually associated with other syndromes like glomerulopathy associated with a monoclonal immunoglobulin or C4 dense deposit disease associated with a monoclonal immunoglobulin. Diagnosis depends or identifying these other syndromes and the identification of complement components on kidney biopsy. Regardless of the exact pathophysiology causing monoclonal immunoglobulin-induced kidney injury, MGRS has a greater morbidity and mortality than other forms of MGUS. Since renal dysfunction usually improves with therapy directed at the underlying plasma cell dyscrasia, MGRS may warrant treatment even when other parameters of plasma cell dyscrasia severity (e.g. low levels of serum monoclonal immunoglobulin and bone marrow plasma cells) suggest the presence of minimal, non-malignant disease. Smoldering multiple myeloma stage
Smoldering multiple myeloma or SMM (also termed smoldering myeloma) is the next stage following MGUS in the spectrum of plasma cell dyscrasias. While still considered a pre-malignant condition, its chances of progressing to a malignant plasma cell dyscrasia are generally greater than that for MGUS.