Exploring the gamut of monoclonal gammopathy of cutaneous significance

By David A. Wetter, MD, FAAD
Sept. 17, 2025
Vol. 7, No. 37

One of our favorite board-review books during my dermatology residency was Dermatology Quick Glance, authored by Drs. Saeed Jaffer and Abrar Qureshi in 2004. My coresidents and I would periodically meet during the few months before the annual in-service exam to review its chapters (which we nicknamed the “Purple Book” due to the color of its cover) and quiz each other about pertinent pearls. In the “High-Yield Factoids” chapter there was a section on “Paraproteinemias Associated with Skin Changes,” and I remember us asking one another in rapid-fire succession, “What condition is associated with IgM kappa monoclonal gammopathy?” (Schnitzler syndrome); “What subtype of monoclonal gammopathy is most commonly seen with neutrophilic dermatoses?” (IgA); “What are the typical paraproteins associated with scleromyxedema and necrobiotic xanthogranuloma?” (IgG lambda and IgG kappa, respectively). But why is it clinically important for us to know the associations between monoclonal gammopathies and skin disorders? First, it may be a clue that allows dermatologists to provide a unifying diagnosis linking a cutaneous eruption with systemic symptoms and cutaneous findings (e.g., diagnosing a patient with a chronic urticarial eruption with elevated inflammatory markers, lymphadenopathy, bone pain, and a monoclonal IgM kappa protein with Schnitzler syndrome [1]). Moreover, in patients with persistent or relapsing skin diseases occurring in the presence of a monoclonal protein, our knowledge of the connection between the skin and the paraprotein can facilitate a multidisciplinary dialogue with our colleagues (particularly hematology-oncology) about whether treatment directed against the paraprotein could be employed as a primary treatment for the skin disease. As one of my colleagues, Mark Pittelkow, MD, once remarked to me when I was a junior faculty, “small clones can do big things in the skin.” (Dr. Pittelkow served as the senior author on a comprehensive review of monoclonal gammopathies and associated skin disorders over a quarter of century ago [2]).

Within the last few years, I saw a referral patient with a painful, purpuric, recalcitrant eruption predominantly on the dorsal hands, that was associated with arthralgias. The workup demonstrated a small IgA kappa monoclonal protein, which, when taken together with other clinical and histopathologic findings, was integral in rendering a diagnosis of erythema elevatum diutinum (EED). Prior to presentation at our institution, the patient’s condition had rapidly responded to dapsone; unfortunately, dapsone had to be discontinued because of a “hypersensitivity reaction.” Other prescribed treatments included colchicine, mycophenolate mofetil, sulfasalazine, sulfapyridine, and methotrexate; these treatments either caused adverse effects (including hypersensitivity-like reactions to sulfasalazine and sulfapyridine) or failed to provide adequate clinical improvement. Given that the EED was significantly diminishing the patient’s quality of life, we pursued targeting the IgA kappa monoclonal protein for the primary purpose of treating the refractory EED in conjunction with hematology. As of this writing we are seeking approval for a plasma-cell directed therapy such as daratumumab.

During my discussions with hematology colleagues, it was necessary to explain why I was recommending a plasma-cell directed treatment for a relatively rare skin condition in a patient who did not have an underlying hematologic malignancy, but only had a small IgA kappa monoclonal protein. Was there common terminology I could utilize in our multidisciplinary conversation to bolster my contention that the best chance of successfully treating the patient’s EED was through targeted treatment of the IgA monoclonal gammopathy?

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Building upon the thorough review of Daoud et al. (2), Claveau and colleagues recently provided an update on the cutaneous manifestations of monoclonal gammopathy. (3) Dermatologic disorders that are a consequence of the monoclonal gammopathy due to infiltration and proliferation of malignant plasma cells in the skin or deposition of proteins related to the monoclonal protein include Waldenström macroglobulinemia cutis, systemic immunoglobulin light chain (AL) amyloidosis, cryoglobulinemia, plasmacytoma, and POEMS syndrome. (2, 3) In contrast, other dermatologic diseases (such as the patient vignette described earlier) are associated with a nonmalignant monoclonal gammopathy due to “deposition of all or part of the monoclonal immunoglobulin, autoantibody activity, cytokine-mediated, or by an unknown mechanism” (3); examples include scleromyxedema, scleredema, necrobiotic xanthogranuloma, plane xanthoma, Schnitzler syndrome, pyoderma gangrenosum, Sweet syndrome, leukocytoclastic vasculitis, neutrophilic dermatosis, erythema elevatum diutinum, and subcorneal pustular dermatosis. (2, 3)

Fernand et al. (4) noted that monoclonal gammopathy is frequently of unknown significance, when it “results from a small and/or quiescent secreting B-cell clone, is completely asymptomatic, and requires regular monitoring only.” However, they recognized “although quiescent and not requiring any treatment per se,” that “even a very small clone can produce severe manifestations due to toxicity of the monoclonal immunoglobulin or other mechanisms” in other organs such as the kidney, peripheral nerve, and skin. (4) Because this scenario is “poorly recognized and frequently undertreated,” Fernand and colleagues proposed the term “monoclonal gammopathy of clinical significance” to “improve early recognition and management of these small B-cell clone-related disorders” (particularly since “efficient control of the underlying B-cell clone usually results in organ improvement”). (4)

One year earlier (in 2017), Lipsker posited that monoclonal gammopathies can have “significant clinical consequences” in some instances. (5) To emphasize that some dermatologic diseases are “strongly associated with the presence of a monoclonal gammopathy,” Lipsker introduced the concept of “monoclonal gammopathy of cutaneous significance” and hoped that this would “pave the way to the broader and unifying concept of monoclonal gammopathies of clinical significance.” (5)

Recently, Gordon et al. performed a retrospective review of 30 patients with cutaneous findings associated with monoclonal gammopathy of undetermined significance (MGUS). (6) Since treatment of the cutaneous “complications with therapies directed toward elimination of the pathogenic clone may be difficult because of lack of insurance coverage and diagnostic recognition” (6, 7), and because the poorly understood nature of the cutaneous findings associated with monoclonal gammopathy oftentimes leads to “diagnostic delays and patient morbidity” (6), they proposed the term “gammopathic dermopathy” to illuminate the “significant cutaneous manifestations of the disease.” (6) The 30 patients were grouped into four disease categories:

• MGUS-associated rashes and pruritus: Pruritus (n=5); eczematous rashes (n=3); urticaria (n=1); and bullous pemphigoid (n=1)

• Reactive and mucin-depositional disorders: Scleromyxedema (n=4); pyoderma gangrenosum (n=2); follicular mucinosis (n=1); granulomatous dermatitis (n=1); and perivascular dermatitis (n=1)

• M-protein deposition disorders: Raynaud phenomenon (n=4); POEMS (n=2); and Waldenström macroglobulinemia (n=1)

• Cutaneous lymphomas: Cutaneous T-cell lymphoma (n=3) and marginal zone lymphoma (n=1) (Note: The authors mentioned that despite the co-occurrence of cutaneous lymphoma and monoclonal gammopathy, the possible relationship between the two is unclear.)

A concurrent study by the same authors sought to assess the response of cutaneous diseases in the aforementioned 30 patients (and one additional patient) to therapy directed against the monoclonal protein with multiple myeloma drugs (MMDs) (7). Of 31 patients, 12 received MMDs (the most common of which were lenalidomide [n=9], daratumumab [n=2], and ixazomib [n=1]). Eleven of 12 (92%) patients who received MMDs had “significant improvement” in their skin disease, while only 3 of 19 (16%) who did not receive MMDs “had even minor improvement” (6, 7). Four of 10 patients with “MGUS-associated rashes and pruritus” received MMDs, with all four experiencing improvements in their skin conditions; similarly, all 6 (of 9) patients with “reactive and mucin-depositional disorders” who received MMDs improved with treatment (6). The authors concluded that “given the frequency of MGUS in older adults, those with intractable pruritus or steroid nonresponsive conditions should be considered for comprehensive evaluation for monoclonal gammopathy.” (7) They also suggested that treatment with MMDs should be considered in patients with monoclonal gammopathy and refractory pruritus or rashes that do not improve with conventional treatments (6).

Point to Remember: Consider using terms such as “cutaneous manifestations of monoclonal gammopathy,” “gammopathic dermopathy,” “monoclonal gammopathy of cutaneous significance,” and/or “monoclonal gammopathy of clinical significance” in your dermatologic practice. These terms emphasize the potentially clinically-relevant relationship between skin disease and the presence of a monoclonal gammopathy; aid in collaborative multidisciplinary discussions; and provide a rationale to consider treating the underlying pathogenic clone with drugs used for multiple myeloma.

Our Editor’s viewpoint

Warren R. Heymann, MD, FAAD

As Dr. Wetter astutely observes, there has been a spike (pun intended) in terms that point to the clinical relevance of what was previously considered an incidental or enigmatic monoclonal gammopathy of undetermined significance (MGUS). The disorders he emphasized — notably scleromyxedema, Schnitzler syndrome, POEMS syndrome, necrobiotic xanthogranuloma with paraproteinemia, and others in which a paraprotein is consistently found and likely to play a pathogenic role — offer a compelling rationale for utilizing multiple myeloma drugs. Despite the validity of terms such as “monoclonal gammopathy of clinical significance” (MGCS), it must be remembered that approximately 5% of adults have MGUS and the cutaneous diseases associated with such paraproteins are very rare. The overwhelming majority of patients with MGUS are not associated with cutaneous disorders and have indolent disease with the risk of progression to malignant disease ranging from 0.5 to 1%. (8) It is our duty as dermatologists to determine if an MGUS is a MGCS depending on the clinical presentation. I encourage clinicians to not only check a serum protein electrophoresis (SPEP) in disorders that are classically associated with a paraprotein but also obtain a SPEP when challenged by a diagnostic conundrum to determine if a paraprotein may be at play.

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References

1. Barbosa NS, Schoch JJ, Ringler MD, Wetter DA. Chronic urticarial eruption associated with monoclonal gammopathy. Am J Hematol. 2015;90:365-6.

2. Daoud MS, Lust JA, Kyle RA, Pittelkow MR. Monoclonal gammopathies and associated skin disorders. J Am Acad Dermatol. 1999;40:507-35.

3. Claveau JS, Wetter DA, Kumar S. Cutaneous manifestations of monoclonal gammopathy. Blood Cancer J. 2022;12:58.

4. Fermand JP, Bridoux F, Dispenzieri A, et al. Monoclonal gammopathy of clinical significance: A novel concept with therapeutic implications. Blood. 2018;132:1478-1485.

5. Lipsker D. Monoclonal gammopathy of cutaneous significance: Review of a relevant concept. J Eur Acad Dermatol Venereol. 2017;31:45-42.

6. Gordon ER, Chen C, Trager MH, et al. Gammopathic dermopathy: Characterization of cutaneous MGUS. Leuk Lymphoma. 2024;65:989-996.

7. Gordon ER, Chen C, Adeuyan O, et al. Retrospective analysis of multiple myeloma drug use in cutaneous toxicity of monoclonal gammopathy of undetermined significance. J Am Acad Dermatol. 2024;91:129-130.

8. Liu Y, Parks AL. Diagnosis and Management of Monoclonal Gammopathy of Undetermined Significance: A Review. JAMA Intern Med. 2025 Apr 1;185(4):450-456. doi: 10.1001/jamainternmed.2024.8124. PMID: 39960681; PMCID: PMC11975479.

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