Dupilumab for the Treatment of Refractory Lenalidomide Rash in Patients with Multiple Myeloma

Lenalidomide (Len) is FDA-approved for the treatment of multiple myeloma (MM). While len is associated with significantly improved progression free survival (PFS) [1], patients frequently require dose interruptions or reductions due to toxicities. Len rash occurs in over a quarter of patients, with 1–7% developing high grade (Common Terminology Criteria for Adverse Events [CTCAE] v5.0 grade 3 or 4) rash. The rash typically presents within the first 2–4 weeks of len [1,2]. Patients who develop len rash have significantly improved PFS and overall survival than those without rash [3,4], underscoring the importance of identifying effective therapies with low toxicity profiles for len rash, so that dose intensity is maintained and patients can achieve the maximum benefit of len [2].

Dupilumab is an IL-4 receptor alpha antagonist with no significant associated severe toxicities for the treatment of atopic dermatitis [5]. We present 6 patients with MM and refractory len rash who were treated successfully with dupilumab and propose a potential mechanism for its benefit.

This single-center, retrospective study was approved by the Institutional Review Board (IRB) of Memorial Sloan Kettering Cancer Center (MSK). A database query was performed to identify patients with MM who developed len rash, which was subsequently treated with dupilumab.

Three patients were receiving treatment with len for induction and three for maintenance, consolidation, or relapse after autologous hematopoietic stem cell transplantation (AHCT) when an associated maculopapular rash developed (median CTCAE grade 2, range: 2–3). Patients were black (n=3) and white (n=3), with a median age of 62 (range: 54–75) years. Five were male. Before starting dupilumab, three patients had experienced len interruption and two experienced dose reduction due to len rash; one patient did not experience either. Three had failed topical steroids, three both topical and oral steroids (Table 1), and all six patients were subsequently treated with subcutaneous dupilumab 600mg loading dose followed by 300mg every two weeks. Of the five patients who experienced len interruption or reduction, one patient was able to resume len at their pre-rash dose and two at a reduced dose once rash was controlled (grade ≤1) with dupilumab. Rash recurred in one patient when len was reintroduced and len resumption was not attempted in another patient (Table 1 & Figure 1A). Four patients had peripheral eosinophilia (median absolute eosinophils 0.3 K/mcL, range: 0.1–1.1 K/mcL; median percent eosinophils 10.1%, range: 3.3–18.4%) at the onset of rash (Table 1). IgE, IL-5, and TNFα were checked in 2 patients and were not elevated. IL-6 was elevated in 1 of 2 patients tested (range of 4.4–9.2 pg/mL).

Table 1:

Summary of patients’ clinical data.

Case	Age/ Sex	At the Time of Rash Onset																		Unsuccessful Treatments for Rash	Supportive Medications with Dupi	Dupi Duration	Result of Dupi Therapy	Adverse Events from Dupi	Len Resumption After Dupi
		History of AHCT	Diagnosis	MM Status	Len Regimen	Use of Len	Len Dose (mg)	Len Interruption or Dose Decrease Due to Rash	Rash Grade	Pruritus Grade	Absolute Eosinophils (K/mcL)	% Eosinophils	IgE (kU/L)	IL-5 (pg/mL)	IL-6 (pg/ mL)	TNFα (pg/mL)	Number of Treatment Cycles Before Rash	Area of Rash	Rash Description
1	67/ F	Yes	Stage III IgG Kappa MM	POD	Len, clinical trial therapy	Relapse	25	No	2	N/A	0.1	4.1	37.4	<1.0	4.4	7	1	Back, arms	Eczematous papules and plaques	Triamcinolone 0.1% cream	Clobetasol 0.05% foam	Continued dupi while on len	Rash resolved	None	N/A
2	62/ M	Yes	Stage III MM	MRD Positive	Single agent len	Maintenance	10	Yes	2	2	0.1	3.3	N/A	N/A	N/A	N/A	1	Back, arms, thighs	Eczematous patches	Alclometasone 0.05% cream, triamcinolone 0.1% cream, prednisone taper	Tacrolimus 0.1% ointment, clobetasol 0.05% spray, pregabalin 50 mg 2x/day	Continues both len and dupi	Rash resolved	None	Yes
3	75/ M	No	IgA Kappa NDMM	VGPR	Car, len, dex	Induction	15	Yes	3	N/A	0.4	11.7 (H)	N/A	N/A	N/A	N/A	3	Scalp, trunk, upper arm	Eczematous patches	Triamcinolone 0.1% cream, prednisone taper	Clobetasol 0.05% spray, tacrolimus 0.1% ointment	Continues both len and dupi	Rash resolved	None	Yes
4	62/ M	No	Stage III IgG Kappa MM	VGPR	Dara, len	Induction, maintenance	15	Yes	3	2	0.8 (H)	9.5 (H)	N/A	N/A	N/A	N/A	1	Generalized	Morbilliform, maculopapular	Triamcinolone 0.5% ointment	Hydrocortisone 2.5% cream, clobetasol 0.05% spray	Continues dupi post-len	Rash resolved but then recurred on len	None	Discontinued due to rash recurrence
5	58/ M	No	Stage II IgG Lambda MM	MRD Negative	Dara, car, len, dex	Induction	25	Yes	2	N/A	1.1 (H)	18.4 (H)	N/A	N/A	N/A	N/A	2	Back of head, trunk, proximal extremities	Morbilliform papules and plaques	Triamcinolone 0.1% cream, prednisone taper	Clobetasol 0.05% spray	Continues both len and dupi	Rash resolved	None	Yes
6	54/ M	Yes	Stage II IgG Kappa MM	POD	Len, dex	Consolidation	25	Yes	2	3	0.2	10.6 (H)	212	<1.0	9.2 (H)	16	1	Fingers, forearms	Eczematous pink papules	Fluocinonide 0.05% cream	Clobetasol 0.05% spray, alclometasone 0.05% cream, pregabalin 50 mg 2x/day, NB-UVB phototherapy 3x/week	Continues dupi post-len	Rash resolved	None	Did not attempt

Len= Lenalidomide, Dupi= Dupilumab, Dara= Daratumumab, Car= Carfilzomib, Dex= Dexamethasone, LD= Loading dose, MRD= Minimal residual disease, POD= Progression of disease, VGPR= Very good partial response

Figure 1:

A) Len course and len rash severity before and after treatment with dupilumab. B) Len rash in patient 4 before starting dupilumab and C) after 1 dose of dupilumab treatment. D) A punch biopsy from the right thigh of patient 4 shows a spongiotic and perivascular dermatitis with an inflammatory infiltrate comprised of lymphocytes, histiocytes and eosinophils (H&E; scale bar in lower left).

Patient 1 developed a steroid refractory rash after len dose increase from 10mg to 25mg. Dupilumab was started, with resolution of rash and she was able to continue len at the higher dose without interruption until she was switched to next line of therapy due to progression of disease (POD), at which point she discontinued both len and dupilumab.

Patient 2 developed rash during his first cycle of len at 10 mg. Len dose reduction to 5 mg and prednisone taper (40mg daily × 4 days, 30mg daily × 4 days, 20mg daily × 4 days, 10mg daily) failed to control his rash and len was interrupted. After starting dupilumab, he was able to resume len at 5mg without prednisone with resolution of rash.

Patient 3 developed len rash at the end of his third cycle of carfilzomib, len15 mg, and dexamethasone 20mg refractory to prednisone taper (10mg daily × 10 days, 5mg daily × 10 days, 5mg every other day × 10 days). Len was interrupted until his rash cleared after 1 month of treatment with dupilumab. He has continued both len 15mg and dupilumab with ongoing very good partial response (VGPR) in MM.

Patient 4 developed steroid refractory rash with len 15mg and daratumumab (Figure 1B). Biopsy showed spongiotic and perivascular dermatitis consisting of lymphohistocytic infiltrate with numerous eosinophils (Figure 1D). Despite discontinuing len, his rash persisted and only resolved after he received dupilumab (Figure 1C). Retrial of len at a reduced dose of 2.5mg per desensitization protocol [6] resulted in rash re-flare and len was permanently discontinued. He continues dupilumab for control of his persistent post-len rash with excellent control (grade 0).

Patient 5 developed len rash while on a clinical trial with daratumumab, carfilzomib, len 25mg, and dexamethasone (Dara-KRd) for induction. He completed 8 cycles of Dara-KRd on prednisone. He started maintenance therapy with len 10mg but his rash flared when prednisone was tapered and treatment was interrupted. After receiving dupilumab, his rash resolved and he has been able to continue dupilumab and resume len 10mg maintenance therapy without the use of systemic steroids and without rash recurrence.

Patient 6 developed steroid refractory pruritus and rash after starting len 25mg and dexamethasone which persisted even after len was held. Dupilumab controlled his post-len rash as he was transitioned to next line of therapy due to POD.

None of these patients treated with dupilumab experienced adverse events attributed to dupilumab (including infections or conjunctivitis).

Recurrent, persistent, or high-grade rash can lead to len dose modifications or discontinuation [7]. Len-associated skin eruptions negatively impact patients’ quality of life. Treatment recommendations for len rashes include oral antihistamines, topical steroids, or low-dose oral steroids. If the rash persists or progresses to grade ≥3, len is typically held, and discontinuation may be considered [7]. Len desensitization has been proposed; however, implementation of desensitization protocols is challenging, with low ability to tolerate prior len dose [8,9]. Because len increases PFS in MM before and after AHCT and len rash is associated with improved PFS and OS in MM, it is critical to identify safe and effective, well-tolerated therapies to manage the rash to avoid len interruption or discontinuation [10]. We provide the first report of patients with refractory len rash successfully treated with dupilumab, allowing most to continue len, after unsuccessful trials of various topical and/or systemic steroids.

While len exerts anti-tumor effects by decreasing production of IL-6 and vascular endothelial growth factor from MM cells, inducing tumor suppression genes, and increasing NK-cell expression [11], len rash may result from an allergic response driven by Th2-axis activation leading to atopy-like rash with associated eosinophilia as seen in our patient series [4]. Len may also elicit new rashes or exacerbate existing atopic disease by suppressing the Th1-inducing capacity of dendritic cells while simultaneously enhancing Th2-mediated responses [4].

As such, it is reasonable that dupilumab, approved for atopic dermatitis, would be effective. Dupilumab is a monoclonal antibody that inhibits both IL-4 and IL-13, reducing Th2 responses [12]. Both in vitro and in vivo evidence suggest Th2 cells do not provide protection against MM and may even promote MM growth and proliferation [13]. Thus, by inhibiting Th2 responses, dupilumab may be therapeutic not only in treating len rashes but has the potential to have beneficial effects on the patients’ underlying myeloma as well.

Dupilumab was maintained throughout len therapy in each of our patients and even continued after len was discontinued in 2 patients for management of post-len rash. Atopic dermatitis studies found that maintenance treatment with dupilumab 300mg every 1–2 weeks resulted in better maintenance than less frequent regimens. Additionally, less frequent dosing resulted in higher rates of anti-drug antibody development [14]. Similarly, continued use of dupilumab while on len may be most beneficial for patients with len rash. When patients discontinue lenalidomide in our practice, depending on their symptomatology, dupilumab is discontinued until 2 weeks after or tapered by reducing dosing frequency until discontinued. For select patients with persistent symptoms after len discontinuation, dupilumab may be continued until resolution of symptoms and then similarly discontinued.

Dupilumab has been associated with injection site reactions, conjunctivitis, blepharitis, and oral herpes [1]. In our patient population, no adverse events developed during therapy that were attributed to dupilumab.

Presently, the approved dosing regimen for dupilumab use in atopic dermatitis is 600mg loading dose followed by 300mg every 2 weeks. This dose was also effective for len rash. Notably, use of len with other monoclonal antibodies such as elotuzumab and daratumumab may exert synergistic effects resulting in enhanced myeloma response. As such, future studies should explore not only an optimal dosing regimen for dupilumab in len rash management but also the possibility that len may interact with dupilumab, another monoclonal antibody.

Currently, len is integral in the management of MM. However, its use may be limited by persistent, symptomatic rash, a common and sometimes high-grade adverse event. In this report, all six patients developed persistent rash from len. After controlling the rash with dupilumab, four patients were able to continue or resume len. No patients experienced adverse events or POD attributed to dupilumab. Prospective studies on the use of dupilumab in patients with len rash are warranted to improve outcomes and quality of life for patients with multiple myeloma on len.