Plasma cell-directed therapies in monoclonal gammopathy-associated scleromyxedema

Abstract

Scleromyxedema is a rare skin and systemic mucinosis that is usually associated with monoclonal gammopathy (MG). In this French, multicenter, retrospective study of 33 patients, we investigated the clinical and therapeutic features of MG-associated scleromyxedema. Skin molecular signatures were analyzed using a transcriptomic approach. Skin symptoms included papular eruptions (100%), sclerodermoid features (91%), and leonine facies (39%). MG involved an IgG isotype in all patients, with a predominant λ light chain (73%). Associated hematologic malignancies were diagnosed in 4/33 patients (12%) (smoldering myeloma, n=2; chronic lymphoid leukemia, n=1; and refractory cytopenia with multilineage dysplasia n=1). Carpal tunnel syndrome (33%), arthralgia (25%) and dermato-neuro syndrome (DNS) (18%) were the most common systemic complications. One patient with mucinous cardiopathy died of acute heart failure. Intravenous immunoglobulin (HDIVig) treatment alone or in combination with steroids appeared to be quite effective in nonsevere cases (clinical complete response achieved in 13/31 patients). Plasma cell-directed therapies using lenalidomide and/or bortezomib with dexamethasone and HDIVig led to a significant improvement in severe cases (HDIVig-refractory or cases with central nervous system or cardiac involvement). The emergency treatment of DNS with combined plasmapheresis, HDIVig, and high-dose corticosteroids induced the complete remission of neurological symptoms in 4/5 patients. Quantitative reverse transcriptase-PCR (RT-PCR) analysis of 6 scleromyxedema skin samples showed significantly higher profibrotic pathway levels (transforming growth factor β (TGFβ) and collagen-1) than in healthy skin. Prospective studies targeting plasma cell clones and/or fibrotic pathways are warranted for long-term scleromyxedema management.

Treatment of scleromyxedema with lenalidomide, bortezomib and dexamethasone: A case report and review of the literature

“…8 Similarly, a retrospective study of 33 scleromyxedema patients showed corticosteroids alone (0.75 mg/kg/day of equivalent prednisone) was successful in only 1 patient out of 3 total. 7 This was similar to our patient as he had treatment failure with oral prednisone alone. Due to its ineffectiveness alone, glucocorticoids are more often used in conjunction with other treatment regimens such as melphalan, methotrexate, thalidomide, hydroxychloroquine, cyclophosphamide, and bortezomib.…”

“…The course of scleromyxedema is unpredictable, especially due to the variable response to treatment and the high relapse rate after cessation of treatment. The overall survival rate at 3 years was reported to be 97% in a recent retrospective study, 7 which is an improvement compared to 76.2% in a previous study 8 …”

“…A recent retrospective study recommended adding bortezomib and dexamethasone or lenalidomide and dexamethasone to IVIG for patients who have IVIG refractory disease. 7 The same study reported the first known case of scleromyxedema patient treated with RVD therapy. The patient had IVIG refractory disease and had treatment failure with IVIG as well as a treatment regimen of bortezomib, cyclophosphamide, and dexamethasone.…”

“…These treatment barriers are significant especially in the setting of requiring long-term maintenance to remain in remission. 7 Other treatments which have reported success with scleromyxedema include thalidomide [21][22][23][24] and autologous stem cell transplantation (ASCT). 25 Thalidomide's mechanism of action in treatment of the disease is not clear but is thought to have antiangiogenic properties that block fibroblast growth.…”

Skleromyxödem

“…In der Literatur ist nur ein Bericht einer Spontanhei lung zu finden [24]. In einer Studie von Rongioletti und Merlo et al [17] [36,37] 2 [17,47] 5 [40,41,[57][58][59] 14 [60][61][62][63][64][65][66][67][68][69][70][71][72][73] -in Kombination 0 0 3 [17,38,47] 0 17 [46,48,49,55,[74][75][76][77][78][79][80][81][82][83][84][85][86] Systemische Kortikosteroide 0 0 2 [17,38] 1 [87] 8 [71,[88][89]…”