Clinicopathologic Features, Pathogenesis, and Treatment of Monoclonal Gammopathy–Associated Myopathies

Monoclonal gammopathy-associated myopathies (MGAMs) are rare yet treatable myopathies that occur in association with monoclonal gammopathies. These myopathies include light chain (AL) amyloidosis myopathy, sporadic late-onset nemaline myopathy (SLONM), scleromyxedema with associated myopathy, and newly reported monoclonal gammopathy-associated glycogen storage myopathy (MGGSM), including the vacuolar myopathy with monoclonal gammopathy and stiffness. All these 4 distinct subtypes of MGAMs typically present in patients aged 40 or older, frequently with a subacute onset of rapidly progressive proximal and axial muscle weakness. Dysphagia and weight loss are often present. Peripheral neuropathy is frequent in AL amyloidosis but is generally absent in other MGAM subtypes unless there is a concurrent paraproteinemic neuropathy. Serum creatine kinase (CK) levels vary across MGAM subtypes. AL amyloidosis myopathy and SLONM are often associated with normal CK levels, whereas scleromyxedema-associated myopathy and MGGSM are often accompanied by hyperCKemia. Muscle biopsy remains the only diagnostic test for MGAMs. Histochemical stains, such as modified Gömöri trichrome, Congo red, periodic acid-Schiff, and Alcian blue, and immunohistochemical stain with α-actinin should be included in the evaluation of patients with suspected MGAMs to identify the pathologic features specific to each MGAM subtype. Although the pathogenesis of MGAMs is not well understood, an underlying immune-mediated mechanism likely contributes to most subtypes, except in AL amyloidosis myopathy, where tissue amyloid deposition and direct light chain toxicity are believed to play a central role. Prompt plasma cell-directed therapy aimed at eliminating the culprit plasma cell clone, such as autologous stem cell transplantation or systemic chemotherapy, is warranted to improve clinical outcomes in AL amyloidosis myopathy and in some patients with SLONM, whereas immunomodulatory therapy may be beneficial in patients with scleromyxedema-associated myopathy, MGGSM, and SLONM.