Plasma cell‐directed therapies induce profound clinical and durable responses in patients with severe or relapsed/refractory scleromyxedema

Abstract

Background

Scleromyxedema (SM) is a rare skin disorder related to monoclonal gammopathy. High dose intravenous immunoglobulins (HDIVIg) are usually used as a frontline therapy with initial efficacy. However, some patients evolve with relapse, refractory state or severe extra‐cutaneous complications such as dermato‐neuro syndrome (DNS) or cardiac involvement.

The objective of the study is to evaluate the use of anti‐plasma cell treatment in these patients in order to obtain a deep and durable dermatological and haematological response.

Methods

We report here eight patients treated with HDIVIg together with anti‐plasma cell therapy including: lenalidomide and dexamethasone (n = 5); bortezomib, cyclophosphamide and dexamethasone (n = 1); daratumumab, lenalidomide and dexamethasone (n = 2).

Results

Combination of HDIVIg with a treatment targeting the monoclonal component led to a high level of haematological remission and drastically improved skin response with an acceptable safety profile in all patients. Moreover, HDIVIg was reduced and stopped in 4 of the 7 patients who achieved complete remission.

Conclusions

The association of lenalidomide and dexamethasone with HDIVIg could improve the treatment of relapsed or severe SM.

In severe forms of monoclonal gammapathy associated with scleromyxoedema with dermatoneuro syndrome and/or cardiac involvement, deep and durable responses allowing IVIG withdrawal could be achieved using anti‐plasma cell therapy, including Imids, anti‐CD38 or proteasome inhibitors.

Why was the study undertaken?

Management of severe forms of monoclonal immunoglobulin associated scleromyxoedema is difficult. Steroids and IVIG often lead to a partial and incomplete dermatological response despite prolonged treatment without any effect on plasma cell clone. Recent progress in anti‐plasma cell therapy led us to use it in this setting.

What does this study add?

This study shows that anti‐plasma cell therapy leads to prolonged complete hematological and dermatological remission, often allowing withdrawal of IVIG without recurrence of severe complications of scleromyxoedema.

What are the implications of this study for this disease understanding and/or clinical care?

This study confirms that efficiently targeting the plasma cell clone led to a dramatic dermatological response and prevented severe complications of scleroxoedema, a disease belonging to the recently characterized monoclonal gammopathy of clinical significance. More importantly, anti‐plasma cell therapies allow withdrawal of IVIG and represent an efficient alternative to suspensive treatment.

INTRODUCTION

Scleromyxedema (SM) is a rare disease usually characterized by a diffuse papular and sclerodermoid eruption frequently associated with a monoclonal gammopathy (90% of cases), in the absence of thyroid disorder. Diagnosis is confirmed by skin biopsy showing dermal mucin deposition, fibroblast proliferation and fibrosis. ¹ The pathophysiology underlying the association of SM and the monoclonal gammopathy (MG) is not known, although the role of TGFβ has been suggested in one study. ² The association of these cutaneous lesions with MG identifies SM as part of the large family of monoclonal gammopathies of clinical significance (MGCS). ³

The recommended treatment of SM is high dose intravenous immunoglobulins (2 g/kg every 4 weeks; HDIVIg).^{2, 4, 5} However, some patients require long‐term maintenance of HDIVIg infusion, or relapse while still on therapy. HDIVIg improves the SM, without altering the level of the serum monoclonal component. Besides skin involvement, severe life‐threatening complications of SM are dermato‐neuro syndrome (DNS) and cardiac involvement. DNS is an acute encephalitis preceded by a flu‐like syndrome with fever, seizures and coma. The treatment consists of high dose of steroids, HDIVIg and plasma exchanges but the risk of recurrence persists.^{2, 6}

In patients with multiple relapses, HDIVIg dependence or with severe complications, targeting the plasma cell clone could reduce the level of monoclonal gammopathy and give rise to longer and deeper haematological and dermatological remission. Small studies have reported efficiency of anti‐plasma cell therapies such as thalidomide^{7, 8}; autologous stem cell transplantation (ASCT) ⁹ ; bortezomib, thalidomide and dexamethasone (VTD) ¹⁰ ; bortezomib, lenalidomide and dexamethasone (VRD) ¹¹ ; lenalidomide alone with HDIVIg^{2, 12} or melphalan. ¹³

Here we present a retrospective study of 8 consecutive patients with SM either HDIVIg refractory or with severe complications, who were treated with anti‐plasma cell therapy and HDIVIg, evaluating the quality of responses and the ability to withdraw HDIVIg.

MATERIALS AND METHODS

From 2016 to 2023, 8 patients with SM were treated with anti‐plasma cell therapy in Saint Louis Hospital, Paris, France.

Dermatological response was evaluated by Saint Louis dermatology physicians with PGA score (physician global assessment), a subjective general clinical assessment ranging from 0 to 2 (0 = no improvement; 1 = partial improvement; 2 = full improvement).

Partial improvement was defined as decrease in skin changes and improvement in systemic symptoms and complete response as no symptoms and no detectable skin lesion on examination.

Hematologic response was evaluated with serum protein electrophoresis (SPEP) and immunofixation according to IMWG criteria. ¹⁴ Haematological complete response (CR) was defined as negative immunofixation.

RESULTS

Clinical and biological characteristics, treatments and responses of the 8 patients are summarized in Table 1. Median age at diagnosis of SM was 54.5 years [33–78] and sex ratio (F/M) was 3. All patients met at least 3 of the 4 Rongioletti and Rebora criteria: papular eruption, mucin deposition, fibroblast proliferation, and fibrosis on skin histology, MG, and the absence of thyroid disease ¹ (Figure 1). Extra cutaneous involvements observed were DNS (n = 5), articular involvement (n = 1), hepatic involvement with hepatomegaly and ascites (n = 1), and cardiac involvement (n = 1). For all patients, the MG presented with low IgG serum level, [median: 4.95 g/L; range: 2–12 g/L]. Two patients presented smouldering multiple myeloma (infiltration of bone marrow by plasma cells between 10% and 20%) at the same time as SM and 4 patients presented a smaller infiltration of plasma cells [range:1%–6%] in the bone marrow. Two patients showed overexpression of cyclinD1 by fluorescence in situ hybridization (FISH) analysis. Median follow up was 75 months [29–158].

TABLE 1.

Clinical and biological characteristics of 8 patients and clinical and haematological responses after HDIVIg and anti‐plasma cell therapy.

	Sex age (years)	Bone marrow (%plasma cell)	SPEP (g/L)	Extra cutaneous involvement	Previous treatments	Clinical response	Duration of remission of last treatment (months)	Anti‐plasma cell treatment	Clinical response	Hematologic best response	Duration of treatment (months)	Duration of remission (months)	Stop HDIVIg	Relapse	Follow‐up (months)
#1	F	1%	4.3	Arthralgia and neurologic (DNS)	HDIVIg	CR	19	Lenalidomide	CR	VGPR	30	32	Yes	Yes	72
	76		IgG lambda					dexamethasone	PGA = 2
#2	M	1%	2	‐	HDIVIg	CR	16	Lenalidomide	CR	CR	38	42 (on going)	Yes	No	141
	79		IgG kappa					dexamethasone	PGA =2
#3	F	20%	4.6	neurologic (DNS)	HDIVIg	PR	8	Lenalidomide	CR	CR	59	63 (on going)	Yes	No	73
	34		IgG kappa					dexamethasone	PGA = 2
#4	F	5%	5.3	Cardiac and neurologic (DNS)	HDIVIg	PR	11	Lenalidomide	PR	RP	15	15	No	Yes	77
	34		IgG lambda					dexamethasone	PGA =1
#5	M	10%	6	neurologic (DNS)	HDIVIg	CR	62	Lenalidomide	CR	VGPR	88	88	Yes	Yes	158
	49		IgG lambda					dexamethasone	PGA = 2
#6	F	6%	12	hepatomegaly	MTX, cellcept, plaquenil	SD	45	VCD	PR	PR	5	21	No	Yes	29
	69		IgG kappa		HDIVIg	PR			PGA = 1
#7	F	2%	6.4	‐	HDIVIg	PR	68	Daratumumab lenalidomide dexamethasone	CR	VGPR	9 (on going)	9 (on going)	No	No	92
	60		IgG						PGA = 2
			Lambda
#8	F	1%	‐	DNS	HDIVIg, thalidomide	CR	4	Daratumumab lenalidomide dexamethasone	CR	VGPR	4 (on going)	4 (on going)	No	No	37
	40		IgG lambda			SD			PGA = 2

Abbreviations: CR, complete remission; DNS, dermato‐neuro‐syndrome; FISH, fluorescence in situ hybridization; HDIVIg, high dose intravenous immunoglobulin; MTX, methotrexate; PGA, physician global assessment; PR, partial remission; SD, stable disease; SPEP, serum protein electrophoresis; VCD, bortezomib cyclophosphamide, dexamethasone; VGPR, very good partial response.

FIGURE 1.

Picture of patients before and after HDIVIg and lenalidomide.

As first line therapy, all patients were treated with HDIVIg (2 g/kg) and showed either complete (n = 3) or partial (n = 5) dermatological response, with no effect on the level of monoclonal gammopathy, as expected. HDIVIg was given every 4–6 weeks during a median time of 27 months [6–84]. One patient (#2) relapsed four times and was HDIVIg dependent.

Of the 5 patients exhibiting DNS during SM relapse (#1‐3‐4‐5‐8), 1 patient (#1) had focal seizures, three had generalized seizures (#3‐5‐8) and one (#4) presented neurosensory disorders with headache, obnubilation and aphasia. Three patients (#3‐5‐8) were treated with therapeutic plasmapheresis (6, 4 and 3 times, respectively), corticosteroid (2 mg/kg) and HDIVIg 2 g/kg. All patients recovered after this first line of treatment.

Patient (#6) presented a liver involvement with hepatomegaly and ascites and no cardiac failure. She had been treated with methotrexate, mycophenolate mofetil and hydroxychloroquin without any effect. After skin remission following HDIVIg, liver involvement was also improved. However, this patient became HDIVIg dependent, with worsening of the dermatological phenotype observed when time between the administration of HDIVIg was increased. At relapse, skin lesions and ascites reappeared.

Patient (#4) presented a probable cardiac involvement, with right ventricular dilatation complicated by tricuspid insufficiency and cardiac failure. A biopsy was not possible due to the high‐risk of perforation. During the follow‐up, cardiac evolution was independent of skin evolution.

Treatment with lenalidomide‐based regimen and HDIVIg

Seven patients (#1‐2‐3‐4‐5‐7‐8) received lenalidomide at the dose of 25 mg orally from day 1 to day 21 of 28 day cycles and dexamethasone (40 mg weekly). Five of these patients had previously developed DNS. Lenalidomide was prescribed with acetylsalicylic acid as thrombo‐prophylaxis, antibio‐prophylaxis and contraception. Two patients (#7‐8) were also treated with daratumumab (anti‐CD38 monoclonal antibody) at a dose of 1800 mg administered subcutaneously once per week (days 1, 8, 15 and 22) during cycles 1 and 2, once every 2 weeks (on day 1) during cycles 3 to 6, and once every 4 weeks thereafter. Anti‐plasma cell treatment was started after recovering from DNS and HDIVIg (2 g/kg every 4 weeks) was pursued.

All patients had haematological response with remission of skin features: 2 patients had partial remission (PR), 3 very good partial response (VGPR) and 3 were in complete remission (Table 1). The average time to first response was 1 month. Regarding the safety profile of lenalidomide, tolerance was manageable with cytopenia grade 1 but no need of dose reduction, and one patient experiencing venous thrombosis (grade 3 according to NCI‐CTC V5.0 criteria). After a median of 12 months,^{11, 12, 13, 14, 15, 16} maintenance therapy with lenalidomide was pursued at the reduced dose of 10 mg from day 1 to day 21 of 28 day cycles and dexamethasone was stopped.

HDIVIg could be decreased in 7 patients who showed complete dermatological remission, with four patients (#1‐2‐3‐5) in haematological response (2CR, 2VGPR) stopping HDIVIg completely after 30, 32, 51, 44 months of anti‐plasma cell treatment respectively. Two patients (#1‐4) relapsed during lenalidomide maintenance (3 and 8 months after decreased lenalidomide). The best haematological responses observed were VGPR and PR respectively. Patient #5 showed a dermatological relapse at 44 months after stopping HDIVIg. Patient #3, who achieved sustained CR, was able to stop lenalidomide 8 months after HDIVIg withdrawal (Figure 1).

Treatment with VCD and HDIVIg

Patient (#6) could not take lenalidomide due to severe facial skin involvement of SM with restriction of mouth opening as well as liver involvement. She received treatment with bortezomib (1.3 mg/m² weekly subcutaneously), cyclophosphamide (750 mg/m² at day 1 intravenously) and dexamethasone (40 mg weekly) (VCD). Partial haematological, cutaneous and hepatic response was achieved after 5 months of treatment. Tolerance of treatment was poor with asthenia, nausea and grade 1 respiratory infection, and the patient declined to continue VCD. HDIVIg was pursued irregularly.

DISCUSSION

This study describes the effectiveness and safety of anti‐plasma cell therapy on relapsed/refractory and severe complications of SM based on 8 patients, which allowed withdrawal of HDIVig in some cases. To our knowledge, this is the first and largest study of this topic with long term follow up.

Anti‐plasma cell treatments have already shown efficacy in MGCS, particularly in renal and neurological disorders.^{3, 15, 16} Given the suspected link between the clinical syndromes of SM and the underlying monoclonal immunoglobulin, specific anti‐plasma cell treatments have been reported in a few case studies.^{2, 9, 10, 11, 12} In this study, plasma cell‐directed therapy led to a better control of the disease, particularly in the event of severe complications like DNS. In 7 patients, lenalidomide treatment induced a deep (3 in CR, 3 in VGPR and 1 in PR) and sustained haematological and dermatological remission.

HDIVIg are rare and expensive human products with supply difficulties, and their use should therefore be limited. In patients with dermatological and haematological remission, a progressive decrease of HDIVIg was achieved, including a complete weaning in four patients together with stopping of steroid. Only 2 patients in haematological PR and VGPR experienced relapse. In all patients, there was a clear correlation between the time of increased monoclonal gammopathy and skin relapse. Lenalidomide is an oral and well tolerated drug effective against tumour plasma cells as demonstrated in several studies in multiple myeloma.^{17, 18} Lenalidomide could also be stopped in one patient after achieving confirmed haematological and dermatological CR and after HDIVIg withdrawal.

We propose a therapeutic approach directly targeting the plasma cell clone in severe forms of scleromyxoedema such as DNS, cardiac involvement and for refractory SM in order to obtain haematological complete remission. Treatment with lenalidomide and dexamethasone in association with HDIVIg may be indicated in these cases to avoid recurrence and to achieve complete haematological remission. Given their safety profile and efficacy in plasma cell dyscrasia, anti‐CD38 monoclonal antibodies may be added to this regimen to improve response and duration of remission. Other anti‐plasma cell therapies, including alternative immunomodulatory agents (such as pomalidomide) or proteasome inhibitors (such as bortezomib) could also be used.

In conclusion, this study suggests that prolonged treatment with lenalidomide should be continued and could allow progressive reduction and eventual cessation of HDIVIg and steroids once complete haematological and dermatological remission has been achieved, even in patients with a history of DNS. ¹⁹

AUTHOR CONTRIBUTIONS

FT, CL, AT and BA designed the study and analysed the data. FT wrote the paper. All authors revised and approved the final manuscript.

CONFLICT OF INTEREST STATEMENT

Pr Arnulf has competing interests with BMS celgene, Dr Talbot has competing interests with BMS Celgene, Dr Brignier has competing interests with BMS Celgene, Janssen and Octapharma, Dr Theves has competing interests with Sanofi and Janssen. The authors Dr Lahuna, Dr Mahevas, Dr Harel, Dr Royer, Dr Lemiale, Dr Parquet, Dr Jachet, Pr Bouaziz and Dr Elessa have no competing interests in this article. No support found this work.

ETHICS STATEMENT

All patients provided informed consent.

Theves F, Lahuna C, Mahévas T, Harel S, Royer B, Lemiale V, et al. Plasma cell‐directed therapies induce profound clinical and durable responses in patients with severe or relapsed/refractory scleromyxedema. J Eur Acad Dermatol Venereol. 2025;39:1011–1016. 10.1111/jdv.20257

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author, Dr Arnulf, upon reasonable request.