More Research Is Needed to Improve MGCS Management, Review Says


A better understanding of the pathogenesis of monoclonal gammopathy of clinical significance would help guide clinicians treating the complex condition.

While there are multiple treatment approaches for monoclonal gammopathy of clinical significance (MGCS), the optimal treatment of patients with this group of disorders is still unclear, according to a review published in Frontiers in Immunology.

MGCS is a rare group of conditions associated with monoclonal gammopathy of undetermined significance (MGUS), a precancerous clonal plasma or lymphoplasmacytic proliferative disorder. The mechanisms of the disease are largely unknown, and diagnosing MGCS can be complicated due to non-specific symptoms, a lack of understanding of its pathogenesis, and complex clinical presentations.

Due to the rarity of some MGUS-related conditions, limited clinical data, and low awareness among clinicians, the optimal management strategy has not been defined yet. However, the 2 main treatment options are (1) chemotherapy with anti-myeloma agents and (2) systemic immunomodulatory or immunosuppressive treatments, such as intravenous immunoglobulin (IVIG), corticosteroids, or biological agents. These treatment options have different therapeutic targets, both of which address potential pathogeneses of MGCS.

Authors of the review conducted an extensive literature search to identify current management strategies for clinical disorders on the MGCS spectrum in the absence of multiple myeloma (MM), Waldenström macroglobulinemia, or other lymphoproliferative disorders.

For neuropathies associated with MGUS, several disease mechanisms have been proposed, mostly related to M protein activity. Treatment options for the various neuropathies often include plasmapheresis, steroids alone or in combination with cyclophosphamide, and IVIG, depending on the subtype of neuropathy.

Cutaneous involvement is common in MGUS, and treatments vary depending on the type of cutaneous manifestation. Managing skin disorders related to MGCS can include treatments such as IVIG, chemotherapies, and immune-modulating agents. Ocular injury is another potential manifestation in patients with MGCS, and possible treatment routes are in line with those of MGUS and MCGS spectrum disorders overall.

Outside of the clinical signs that have been identified in past research, the review authors highlight acquired C1 inhibitor deficiency, acquired von Willebrand disease, and crystal-storing histiocytosis as conditions potentially associated with MGUS that warrant further research.

Overall, the review emphasizes the need for further research into optimal management of MGCS, as the currently used myeloma-targeting agents or immunosuppressive and immunomodulatory agents address disease mechanisms that are not fully understood.

“Future studies are required to deepen our understanding of the pathogenesis of MGCS, which may guide us through the path of finding the optimal treatment for this complex yet intriguing clinical spectrum concerning multiple medical disciplines,” the authors concluded.


Oganesyan A, Gregory A, Malard F, et al. Monoclonal gammopathies of clinical significance (MGCS): In pursuit of optimal treatment. Front Immunol. 2022;13:1045002. Published online November 23, 2022. doi:10.3389/fimmu.2022.1045002

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