M-protein–related disorders: MGCS

In this issue of Blood, Fermand et al report that not all cases of monoclonal gammopathy of undetermined significance (MGUS) are truly undetermined. Some patients with a low tumor burden monoclonal gammopathy (MG) have organ damage that requires therapeutic intervention, which the authors call monoclonal gammopathy of clinical significance (MGCS).¹ 

MGUS is a frequent age-related condition found in about 3% of individuals older than age 50 years.²  It consists of the unexpected finding of a small serum or urine M protein, which per se does not require therapy. Individuals with MGUS are observed after they have been diagnosed because an average of 1% of the tumors per year transform into a malignant condition.^3,4  However, in some cases, the small monoclonal clone can cause severe organ or tissue damage.^5-7  Unfortunately, little attention has been paid to this possibility. In many instances, the damage is not recognized as being the result of the MG and, consequently, these patients are undertreated. Fermand et al (experts in the field of MG) report on a new concept termed MGCS to highlight the potential causal relationship between a small monoclonal clone, mainly in individuals with MGUS, and the resultant tissue or organ damage. The authors present the different categories of MGCSs on the basis of the mechanism of tissue injury rather than per organ involvement. These mechanisms are diverse, such as deposition of monoclonal immunoglobulin (MIg; organized as fibrils or crystals or nonorganized), development of autoimmune disorders, activation of the complement alternative pathway, absorption of active molecules, or secretion of cytokines. The organs or systems involved with MGCS include kidneys, peripheral nerves, skin, eyes, and hemostasis resulting in bleeding disorders.

Renal damage linked to the M protein can result in the deposition of glomerular amyloid fibrils, MIg deposition disease, proximal tubulopathy with Fanconi syndrome (κ crystalline inclusions in proximal tubular cells with hypouricemia, aminoaciduria, osteomalacia, and slowly progressive renal failure), glomerulonephritis (GN) as a result of type I or II cryoglobulinemia, proliferative or fibrillary GN with Ig deposits or immunotactoid GN, and C3 glomerulopathy (including C3 GN and C3 dense deposit disease). Most of these conditions present with glomerular proteinuria and progressive renal failure. Renal biopsy is crucial for the appropriate diagnosis. In patients with MGUS and peripheral neuropathy (PN) who have no evidence of amyloid light-chain (AL) amyloidosis or polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, a causal relationship must be considered. In the IgM type, a gammopathy-associated PN is likely (50% have anti-myelin–associated glycoprotein activity), whereas a chronic inflammatory demyelinating polyneuropathy with a coincidental MGUS is the most likely diagnosis in the IgG and IgA types.

The main skin conditions related to M proteins are cryoglobulin (IgG/IgM) vasculitis with petechiae, purpura, or ulcers; Schnitzler syndrome (mostly IgM with chronic urticaria, recurrent fever, arthralgia, and neutrophilic leucocytosis); pyoderma gangrenosum (IgA, ulcers with central necrosis); necrobiotic xanthogranuloma (IgG with yellow subcutaneous papules, plaques, or nodules mainly in the periorbital area, legs, arms, and chest); scleromyxedema (IgG-λ with mucine dermal deposition and occasional systemic involvement with cardiomyopathy, pulmonary fibrosis, or reduced esophageal motility), and acquired generalized cutis laxa (mostly IgG and IgG-λ with elastolysis of the skin resulting in premature aging, occasionally associated with fibrillary glomerulopathy and heart or lung involvement).

The most frequent ocular M-protein–related condition is crystalline keratopathy consisting of Ig deposition, corneal thickening, photophobia, and finally visual loss. Bleeding can result from factor X deficiency in AL amyloidosis, acquired factor VIII deficiency leading to von Willebrand disease, or by impaired platelet aggregation induced by the M protein.

Given the high prevalence of MGUS in the elderly with nonrelated comorbid diseases, the diagnosis of MGCS requires the reasonable exclusion of a chance association. A biopsy to demonstrate the monoclonal Ig in the affected organ or tissue and the appropriate immunohistologic and electron microscopy studies must be performed. Autoantibody titers, serum complement levels, cryoglobulin determination, factor X and factor VIII measurements, and platelet aggregation studies can be also helpful. In several cases, such as in Schnitzler syndrome, pyoderma gangrenosum, or scleromyxedema, the association is supported only by epidemiologic data. Despite an extensive evaluation, including organ or tissue biopsy, in some cases in which an association between the M protein and the organ injury is highly suspected, no definitive evidence of causality has been found. These cases require a careful multidisciplinary evaluation (ie, hematologist plus nephrologist or hematologist plus dermatologist) to decide whether or not to treat the MG. In cases that are highly suspicious, a short treatment test such as 2 or 3 courses of bortezomib and dexamethasone (with treatment continuation in case of a favorable response) would be most reasonable.

In summary, the introduction of the novel concept of MGCS is important because it can increase clinicians’ awareness of the fact that a small amount of M protein can cause several severe clinical conditions. When suspected, the causal relationship between the M protein and organ or tissue damage must be promptly investigated. Finally, if a causal relationship is proven or highly suspected, therapy against the plasma cell clone (rituximab-based in IgM types and bortezomib-based [including autologous stem cell transplantation] in non-IgM types) should be initiated.