Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare disease, which is considered as a paraneoplastic manifestation due to the underlying plasma cell neoplasm.1 All patients present with polyneuropathy, which is typically demyelinating, and monoclonal paraprotein, which is typically of λ isotype. The presence of one of the other major criteria and one of the 6 minor criteria is also required. The major criteria include Castleman disease, sclerotic bone lesions and elevated vascular endothelial growth factor levels (VEGF), whereas the minor criteria include organomegaly, extravascular volume overload, endocrinopathy, skin changes, papilledema, and thrombocytosis.1,2 POEMS is an orphan disease and there is no consensus on the optimal treatment strategy. Herein, we report 2 cases who received upfront treatment with the novel triplet combination of daratumumab (16 mg/kg, weekly for cycles 1–2, biweekly for cycles 4–6, monthly for cycle 7 onwards), lenalidomide (25 mg d1-21 every 4 weeks) and dexamethasone (40 mg weekly) (Dara-Rd). All patients provided written informed consent, and approval by our institutional review board was obtained.
A 62-year old man presented with muscle weakness and neuropathic pain of upper and lower extremities which had been progressively deteriorating during the last 8 months. He also reported skin hyperpigmentation during the past year. Previous treatment with anti-epileptics was deemed ineffective. He had a broad-based gait, bilateral drop foot and bilateral hand paresis. Tendon reflexes both in hands and feet were abolished bilaterally. The Romberg sign was positive, whereas the electromyoneurography was indicative of sensomotor polyneyropathy. The magnetic resonance imaging (MRI) of the brain was suggestive of diffuse cerebral atrophy without focal lesions and the MRI of the lumbar spine indicated a pathological fracture in the T12 vertebrae. The T12 biopsy demonstrated an infiltration of the bone marrow by CD138+ monoclonal plasma cells. Both serum and urine immunofixation were positive for monoclonal IgAλ paraprotein and λ light chain, whereas the bone marrow biopsy showed a 5% invasion by monoclonal plasma cells. The patient had also mild thrombocytosis, an IgA level of 480 mg/dl and a λ free light chain (FLC) level of 51.1 mg/L. The VEGF levels were at 1560 pg/ml (normal range 57.4–445 pg/ml). The hormonal evaluation was within normal limits. The whole body low dose computed tomography (WBLDCT) scan showed sclerotic lesions of the spine, especially in the thoracic vertebrae, and in the right iliac crest. No osteolyses were evident. The abdominal CT scan did not show any organomegaly. Pulmonary function tests confirmed muscle weakness, whereas the diffusion tests were within normal limits. Cardiac ultrasound did not show any pericardial effusion and the estimated ejection fraction was above 50%. The patient initiated treatment with Dara-Rd. Importantly, the locomotor and pain symptoms from upper extremities had been resolved until the end of the first cycle of treatment. A gradual improvement of the symptoms of the lower extremities was evident, as well. Following three cycles of Dara-Rd, patient symptoms had been completely resolved except for a grade 1 residual sensory neuropathy of the lower extremities. The VEGF levels showed a rapid decrease to 224 pg/ml, whereas the IgA levels were 31.2 mg/dl and the λFLC levels were 9.12 mg/L. Both serum and urine immunofixation were negative. The adverse events were manageable and included anemia, neutropenia and constipation. The patient has completed 10 cycles of therapy and remains in hematological and clinical remission.
A 58-year old man presented with gait disturbances and difficulty in fine movements, which had been progressively deteriorating during the past 2 months. The patient reported also a burning sensation in the right limbs during the past 6 months, along with a gradual hyperpigmentation of the skin and an unintentional weight loss of 8 kilograms. The electromyoneurography revealed severe sensory axonal polyneuropathy along with muscle damage. The tendon reflexes were abolished in both legs and there was peripheral muscle weakness, as well. Whole body CTs revealed hepatomegaly and diffuse abdominal lymphadenopathy, whereas no osteolytic or osteosclerotic bone lesions were identified. Bone scan and PET/CT were negative. The serum and urine immunofixations were indicative of IgGκ and κ light chain monoclonal bands, respectively. The bone marrow biopsy showed a 20% invasion by monoclonal plasma cells. The VEGF levels were 1647 pg/ml, whereas the patient presented also thrombocytosis, and the IgG and κFLC levels were 2050 mg/dl and 56.4 mg/L, respectively. Until the completion of the workup, the patient was unable to move and became bedridden. The patient started treatment with Dara-VRd and at the end of the third cycle the VEGF levels were decreased to 379 pg/ml, whereas the thrombocytosis had been resolved. The clinical condition of the patient had been gradually improving and he had begun to stand upright. Following the completion of the sixth cycle of treatment, the VEGF levels were further decreased to 155 pg/ml and both the serum and urine immunofixations were negative. The performance status of the patient had been further improved and the patient was able to carry out everyday activities. The regimen was well tolerated without any dose modifications. The patient has now received 13 cycles of treatment, he is in clinical and hematological response and the VEGF has fallen to 46.5 pg/ml. Neuropathy has now improved to grade 1 and the patient is able to walk without support in a broad basis.
The management of patients with POEMS syndrome is risk-adapted; radiation for patients with a localized lesion and systemic therapy aiming at the underlying cause for those with disseminated disease. Alkylators and lenalidomide-dexamethasone (Rd) are considered the mainstay of therapy, whereas bortezomib and thalidomide may be avoided due to the risk for neuropathy.1,2 Autologous stem cell transplantation (ASCT) should be considered only for fit patients, all of whom derive clinical benefit.1,2 Lenalidomide results in hematological and biomarker response along with improvement in neuropathy for the majority of patients; however, the complete response rate is below 20%.3 Taking into consideration the high efficacy of Rd among patients with POEMS along with the superiority of Dara-Rd compared with Rd among patients with multiple myeloma in the MAIA and POLLUX studies,3–9 we opted to administer Dara-Rd in our patients. Interestingly, it has been reported that the administration of Dara-Rd in a patient with relapsed/refractory POEMS following ASCT has resulted in complete hematological remission, normalization of VEGF levels and clinical improvement.10 Collectively, these results are suggestive of a proof-of-concept framework showing that Dara-Rd is safe and highly effective for both newly diagnosed and relapsed/refractory patients with POEMS. Importantly, this regimen provides rapid, deep and durable responses and significantly restores the functionality enabling patients to engage into their everyday activities. Currently, ASCT remains the treatment of choice for fit patients because of the prolonged remission observed afterwards1,2 and the financial burden of maintaining Dara-Rd which is about $260,000 for one year of treatment. Although randomized controlled trials may be difficult to be conducted due to the rarity of the POEMS syndrome, Dara-Rd should be further evaluated in prospective clinical studies.
1. Dispenzieri A. POEMS syndrome: 2017 update on diagnosis, risk stratification, and management. Am J Hematol.
2. Gavriatopoulou M, Musto P, Caers J, et al. European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias. Leukemia.
3. Zagouri F, Kastritis E, Gavriatopoulou M, et al. Lenalidomide in patients with POEMS syndrome: a systematic review and pooled analysis. Leuk Lymphoma.
4. Facon T, Kumar S, Plesner T, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med.
5. Dispenzieri A, Klein CJ, Mauermann ML. Lenalidomide therapy in a patient with POEMS syndrome. Blood.
6. Vannata B, Laurenti L, Chiusolo P, et al. Efficacy of lenalidomide plus dexamethasone for POEMS syndrome relapsed after autologous peripheral stem-cell transplantation. Am J Hematol.
7. Royer B, Merlusca L, Abraham J, et al. Efficacy of lenalidomide in POEMS syndrome: a retrospective study of 20 patients. Am J Hematol.
8. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med.
9. Dimopoulos MA, San-Miguel J, Belch A, et al. Daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of POLLUX. Haematologica.
10. Khan M, Stone K, van Rhee F. Daratumumab for POEMS syndrome. Mayo Clin Proc.