First-line therapy with daratumumab, lenalidomide and dexamethasone for patient with POEMS syndrome: A case report

Abstract

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M–protein, skin changes syndrome) is a rare condition due to an underlying plasma cell neoplasm whose clinical presentation can be various so it could lead to delayed diagnosis and treatment. The pathogenesis of the syndrome is not well understood, and its therapy is adapted from other plasma cell disorders with the aim of alleviating symptoms, decreasing end-organ damage, improving quality of life and prolonging overall survival. We report a case of a 71 years-old woman who has been treated with continuous DRd (daratumumab, lenalidomide and dexamethasone) scheme.

1. Background

POEMS Syndrome (polyneuropathy, organomegaly, endocrinopathy, M–protein, skin changes syndrome) is a rare multiorgan paraneoplastic syndrome resulting from an underlying clonal plasma cell dyscrasia (PCD) [1,2]. Other important features are papilledema, extravascular volume overload, sclerotic bone lesions, thrombocytosis/erythrocytosis, elevated vascular endothelial grow factor (VEGF) levels, a predisposition towards thrombosis and abnormal pulmonary function tests [3]. The diagnosis of POEMS syndrome requires three of the major criteria, two of which must include polyradiculoneuropathy and clonal PCD, and at least one of the minor criteria (Table 1).

Table 1.

Criteria for the diagnosis of POEMS syndrome [3].

Mandatory major criteria	Polyneuropathy (typically demyelinating) Monoclonal plasma cell-proliferative disorder (almost always λ)
Other major criteria	Castelman disease Sclerotic bone lesions Vascular endothelial growth factor elevation
Minor criteria	Organomegaly (splenomegaly, hepatomegaly or lymphadenopathy) Extravascular volume overload (edema, pleural effusion or ascites) Endrocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic) Skin changes (hyperpigmentation, hypertricosis, glomeruloid hemangiomata, plethora, acrocyanosis, flushing, white nails) Papilledema Thrombocytosis/polycythemia
Other symptoms and signs	Clubbing, weight loss, hyperhidrosis, pulmonary hypertension/restrictive lung disease, thrombotic diatheses, diarrhea, low vitamin B12 values

The pathogenesis of POEMS syndrome is still unclear. Even if the role of VEGF in the pathogenesis of POEMS remains not well understood, it is known that this cytokine correlates with disease activity [2,3]. The VEGF is a pro-inflammatory cytokine produced by plasma cells, bone marrow microenvironment and endothelial cells that contributes to vascular permeability and angiogenesis [1]. Dosing VEGF serum levels could be used for diagnosis and monitoring hematological response in patients on active treatment [3]. However, although VEGF levels decrease with therapeutic intervention, there may not be a direct correlation with clinical response [4]. Plasma and serum levels of VEGF are markedly elevated in patients with POEMS and correlate with the activity of the disease. VEGF expressed is VEGF165 and the level of VEGF are independent of M-protein size [3].

According to the rarity of the disease, limited data is available to guide treatment and therapeutic recommendations are mainly based on retrospective data, case reports and small case series [3,5]_. The aim of therapy is to eliminate the underlying plasma cell disorder since the depth of hematological response determines progression free survival (PFS) [4].

Despite the relationship between disease response and dropping levels of VEGF, no successful outcomes has been associated with the use of therapy targeting VEGF, such as anti-VEGF antibodies [3].

2. Case presentation

In January 2022, a 71 years-old woman was admitted to our Hematology Department with history of hypoesthesia and weakness of the lower limbs associated to polycythemia (Hb 17.5 g/dl, Hct 53 %) and thrombocytopenia (platelets count 480.000/mm³).

The myeloproliferative neoplasms driver mutations such as JAK2V617F, CALR and MPL were absent, while JAK2 exon 12 was not assessed.

An IgA- λ monoclonal component was detected in serum and a fully hematological MM work up was pursued. The remaining blood tests were otherwise normal with no CRAB criteria detected (hypercalcemia, renal insufficiency, anemia and bone lytic lesions). A bone marrow biopsy showed the presence of 10 % of restricted CD138+ plasma cells for λ light chains. In addition, the proliferation of the megakaryocyte series and lymphoid follicles with Castelman-like aspects was observed. No figures referable to amyloid deposit was demonstrated neither in the bone marrow nor in the fat pad aspirate. Abdomen ultrasound showed splenomegaly (DL 12 cm). Cardiac ultrasound did not show any pericardial effusion and the estimated ejection fraction was above 56 %.

The radiological examination with whole body PET-TC scan resulted negative for the presence of sclerotic bone lesions and lymphadenopathies. The endocrinological evaluation and pulmonary function tests were both normal. Electromyography (EMG) and electroneurography (ENG) showed a severe sensory-motor demyelinating neuropathy with secondary axonal damage, symmetrical and with a length-dependent distribution associated with signs of chronic neurogenic suffering with denervation activity in the tibialis anterior muscles.

Considering the suspicion diagnosis of POEMS syndrome, serum VEGF levels were determined (2047.8 pg/ml) and it was above the limit of normal range (normal range 62–707 pg/ml).

Since the diagnosis of POEMS syndrome was confirmed considering the presence of both major mandatory criteria, the presence of one major criterion and two minor criteria, the patient immediately started anti-plasma cell treatment, according to DRd scheme (daratumumab, lenalidomide and dexamethasone) [9]. After the first cycle of therapy, the patient showed the complete resolution of polycythemia and thrombocytopenia and the initial monoclonal protein clearance. Nevertheless, our patient experienced hematological toxicity related to treatment and grade 3 neutropenia without infectious complications was observed. Unfortunately, due to the recurrent episodes of severe neutropenia the patient progressively reduced the dosage of lenalidomide up to 5 mg daily starting from the fourteenth cycle of therapy.

Considering the neurological symptoms related to POEMS syndrome, EMG and ENG were repeated after six cycles of therapy, and it showed an improvement of motor and sensory electrophysiological parameters compared to the diagnosis, with an increased amplitude of the compound muscle action potentials (CMAPs) assessed at ulnar and median nerves of both upper limbs.

The last neurological evaluation was carried out after twenty-three cycles of therapy and demonstrated a further improvement in the CMAPs at the level of the sural, peroneal and plantar nerves of both lower limbs, too. Nevertheless, the patient experienced a modest improvement in the strength deficit in the lower limbs, currently equal to 3/5 associated with a persistence of tactile and painful hypoesthesia.

Serum VEGF levels, measured after the twenty-fourth cycle of therapy, decreased to 220.70 pg/ml, within the limits of normal range.

3. Discussion

The treatment armamentarium in POEMS syndrome is borrowed from other plasma cells disorders [3].

In a systematic review on the efficacy and safety of regimen used for the treatment of POEMS syndrome, Faizan et al. [5] showed that most studies highlight the therapeutic potential of different classes of drugs including immunomodulatory drugs (IMIDs), proteasome inhibitors (PIs) and alkylating agents. Specifically, lenalidomide in combinations with corticosteroids seems to be the most commonly studied association with its widely immunomodulatory and antitumor effects. It is associated with reasonable efficacy with 75 to 95 % of patients experiencing significant clinical and biochemical improvement [5]. However, for autologous stem cell transplantation eligible patients, long-term use of lenalidomide may impair stem cell mobilization and collection. About thalidomide, sensory neuropathy and cardiotoxicity are some of the prohibitive toxicities for its use in patients with POEMS syndrome [5]. Furthermore, according to specific peripheral neurotoxicity, bortezomib should be limited in patients without significant neurological symptoms [5]. In a multicenter analysis on 108 patients affected by POEMS syndrome Jurczyszyn et al. [4] showed that, although bortezomib may be associated with peripheral neuropathy, the potential benefits of proteasome inhibitors seem to overcome the risk of bortezomib-associated neuropathy. Upfront therapy with PIs, predominantly bortezomib, achieved a 69 % of complete response or very good partial response (CR/VGPR) rate, which was the most efficacious treatment reported. In the same study, IMIDs based therapy resulted in a 44 % of CR/VGPR rate [4]. Thalidomide and bortezomib have activity, but their benefit needs to be weighed against their risk of exacerbating the peripheral neuropathy [3]. Dispenzieri et al. [3] suggested that the application of neurotoxic multiple myeloma-based therapies should be used only in the context of a clinical trial or at the time of relapsed or resistant disease. In transplant eligible patients, ASCT is considered a part of front-line therapy. The differences in CR/VGPR rates were superior in ASCT versus non-ASCT cohorts (52 % versus 35 %, respectively; p = 0.003), with a trend towards better PFS and overall survival (OS) in the ASCT group [4].

To our knowledge, our report is the fourth case about front-line therapy with continuous DRd in POEMS syndrome reported in literature. The first case reports of daratumumab-based combinations in patients with POEMS syndrome were promising with hematologic, VEGF and neurologic documented improvement [3,6,7]. Lenalidomide might be highly effective in POEMS syndrome's patients not only inhibiting tumor cells growing, but also regulating the production of VEGF [6]. Furthermore, lenalidomide induces CD38 expression on plasma cells, and immunosuppressive cells, and could increase daratumumab efficacy [6].

About our patient, considering the previous reported high efficacy and safety of Rd in patients with POEMS syndrome [7], and considering the available data of MAIA trial [8] in non-transplant eligible multiple myeloma patients, we decided to immediately treat our patient according to DRd scheme.

About the other available first-line therapy in non-transplant eligible multiple myeloma patients such as D-VMP (daratumumab, bortezomib, melphalan, prednisone) [9], according with data reporting in the literature [3,4], we preferred not to use this scheme also because we would not be able to monitor any worsening of the bortezomib-related neuropathy.

Dispenzieri et al. [3] underlined how there is a lag between completion of successful therapy and neurologic response, often with no discernible improvement until six months after completion of therapy, with maximal peripheral nerve response which is not seen until 2–3 years hence. Response criteria for POEMS syndrome could be abridged as follows: (1) hematologic response using a modified amyloid response criterion; (2) VEGF response; (3) 18 FDG-PET response; (4) and a simplified organ response [3].

According to POEMS syndrome response criteria [3], our patient achieved a significant hematological and clinical improvement with DRd treatment. The management of patients with POEMS syndrome is oriented towards the elimination of plasma cell clone with regimens used in other plasma cell dyscrasias with the aim of alleviating symptoms, decreasing end-organ damage, improving quality of life and prolonging overall survival rather than healing. Currently, ASCT remains the first treatment choice in fit patients as it leads to prolonged remissions and it correlates with the improvement of the various clinical aspects that characterize the syndrome.

DRd would appear to be a safe and effective therapeutic strategy both in newly diagnosed patients and in relapsed/refractory patients.

Although randomized controlled trials may be difficult to conducted due to the rarity of the POEMS syndrome, DRd treatment should be further evaluated in prospective clinical studies [10].

Funding information

The authors did not receive funding from any organization for the submitted manuscript.

Informed consent

Written informed consent was obtained from the patient, including permission for the publication of the image.

CRediT authorship contribution statement

E. Amabile: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Resources, Funding acquisition, Data curation, Conceptualization. F. Fazio: Writing – review & editing, Visualization, Validation, Supervision, Data curation. M. Martelli: Visualization, Validation. MT. Petrucci: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Resources, Funding acquisition, Data curation, Conceptualization.

Declaration of competing interest

No potential conflict of interest was reported by the authors.

Data availability

• The data are available from the corresponding author upon reasonable request.