Efficacy of lenalidomide plus dexamethasone for POEMS syndrome relapsed after autologous peripheral stem‐cell transplantation
Authors: Barbara Vannata, Luca Laurenti, Patrizia Chiusolo, Federica Sorà, Mario Balducci, Mario Sabatelli, Marco Luigetti, Claudia Giannotta, Valerio De Stefano, Giuseppe Leone, Simona Sica
Journal: American Journal of Hematology (2012)

POEMS syndrome is a rare paraneoplastic condition associated to an underlying plasmacellular dyscrasia. The pathogenesis of POEMS is poorly understood, but overproduction of VEGF, probably secreted by clonal plasma cells, is thought to be responsible for the signs and symptoms of the syndrome, and it seems to be useful for the monitoring of the response to therapy. At present, an effective therapeutic option for the patients is represented by autologous peripheral blood stem-cell transplantation (aPBSCT), although relapses have been described, and there is an important morbidity associated with this procedure. Before the implementation of aPBSCT, the clinical course of POEMS syndrome was characterized by progressive polyneuropathy potentially leading to death for respiratory failure. Given the high serum and plasma levels of VEGF observed in POEMS patients, the use of antiangiogenetic drugs such as thalidomide and lenalidomide and other drugs with anti-VEGF and anti-TNF effect such as bortezomib have been considered to treat this syndrome. There are evidences of lenalidomide benefit in both front-line and previously treated patients, but scanty data are available about its use for relapse after aPBSCT. Here, we report the successful use of lenalidomide in a patient who relapsed after aPBSCT. POEMS is the acronym referring to the main features of the syndrome: polyradicoloneuropathy, organomegaly, endocrinopathy, monoclonal plasma-cell disorder, and skin changes [1-4]. There are also other typical findings of this syndrome including papilledema, extravascular overload, sclerotic bone lesions, thrombocytyosis/erythrocytosis and elevated VEGF levels, thrombotic diathesis, and abnormal lung function tests, not comprised in the acronym or diagnostic criteria, but with known prognostic value [4, 5]. First-line therapy for patients affected by POEMS syndrome is not well established. Nowadays, for fit patients, the use of alkylating agent and aPBSCT seems to be the best strategy in POEMS [6-13]. For unfit patients, in which the high-dose therapy is not recommended, many therapeutic approaches have been suggested: steroids, low-dose alkylators associated with steroids, radiotherapy. Moreover, new agents were recently investigated including thalidomide, lenalidomide, bortezomib [14, 15], and bevacizumab [16-18]. Lenalidomide, an immunomodulatory drug with a mechanism of action comprising both tumoricidal and immunomodulatory effects has been tested with good results in untreated and pretreated POEMS patients [19-21, 23]. Lenalidomide is generally preferred to thalidomide and bortezomib because of their significant neurological toxicity. Its use is based on the assumption that POEMS is a cytokine-mediated syndrome. VEGF appears to be the main cytokine in this disorder. It is an endothelial mitogen and an angiogenic factor, which increases vascular permeability. Other cytokines include tumor necrosis factor-alpha (TNF-α), interferon gamma (IFN γ), interleukin-1β (IL-1β), and interleukin-6 (IL-6). IL-1 β and IL-6 are both able to stimulate the VEGF production [24]. In multiple myeloma (MM), the association of lenalidomide and dexamethasone showed efficacy even in patients with IgA M-protein, with poor performance status, in the presence of neuropathy and also for patients previously receiving aPBSCT [25] Here, we describe a case of a 52-year-old man admitted to our department on 2003. He was diagnosed with symmetrical peripheral sensorimotor polyneuropathy: he presented with muscle weakness with stepwise progression to tetraplegia accompanied by loss of weight and pain to the extremities. EMG showed an axonal and demyelinating polyneuropathy more severe in lower limbs. At the moment of admission, the laboratory tests displayed the presence of IgAλ monoclonal gammopathy, normochromic normocytic anemia, hypothiroidism. Bone-marrow fine-needle aspiration showed normal plasma-cell count. On physical examination, he also showed splenomegaly, hyperpigmantation, and sclerodermic changes of the skin, and the X-ray of the bone pointed out the presence of several lytic lesions of the spine and ribs and a wide osteosclerotic lesion of the left homerus with extention to the surrounding soft tissues. He started therapy with prednisolone and cyclophosphamide followed by peripheral stem-cell harvest and autologous stem-cell transplantation after Melphalan 200 mg/m2 as conditioning regimen on April 2004 [6]. After transplant, complementary radiotherapy to the left homerus was administered. He obtained a hematologic partial remission [26-29], with the persistence of serum M-protein detected by immunofixation and a consistent improvement of the neuropathy with ability to walk and disappearance of pain. Then, he was followed for 6 years as outpatient, maintaining a hematologic partial response until June 2010. At that time, the patient was admitted to the hospital for anasarca, dyspnea and orthopnea, weight loss, weakness, and recurrence of pain to the lower limbs (ECOG performance status 4, ADL index 2/6). He was unable to walk. He also showed further pelvic, vertebral and femoral lesions, hyperpigmentation, and sclerodermic changes of the skin with fingernail clubbing. Plasma VEGF level at relapse was 1,629 pg/ml (normal range, 0–1,000 pg/ml). Because of his poor performance status, high-dose chemotherapy was not a feasible option: we started lenalidomide/dexamethasone (lenalidomide 25 mg days 1–21 and dexamethasone 40 mg once weekly). After first cycle, the patient showed a sudden improvement of fluid overload with resolution of ascites and dyspnea, but persistence of skin hyperpigmentation and no change of neurological symptoms. Nevertheless, we were able to discharge him after second cycle of therapy. After four cycles, he obtained a significant response with disappearance of splenomegaly and a slight improvement of the skin melanosis, while immunofixation showed the persistence of monoclonal component IgAλ. We observed the disappearance of M-protein after six courses of lenalidomide and plasma VEGF dosage done after the eighth Len–Dex cycle was normal as well as thyroid function. Also, neurological impairment improved gradually. After the sixth cycle, the patient was able to walk with bilateral support, and after the 10th cycle, he could walk independently (Table I). PET–CT scan showed the presence and persistence of increased FDG uptake to the bone lesions with SUV max of 11.6 to the left femur. After his 10th cycle, radiotherapy was administered to both his femora, to the pelvis, and to the T10 bone lesion (30 Gy) based on FDG uptake on FDG–PET/CT scan. At this point, he was able to walk easily, and his ADL index was 4/6. Three months after radiotherapy, lenalidomide was reintroduced because of reappearance of high plasma VEGF levels (2,574 pg/ml) even if no further manifestations of the disease were detected with a follow-up of 19 months after relapse. Lenalidomide was the only feasible therapeutic option for our relapsed POEMS patient, unfit for chemotherapy-based regimens. The response to lenalidomide was prompt and progressive, allowing a marked improvement of functional scales. Some reports suggest efficacy of lenalidomide in POEMS syndrome both in untreated patient unsuitable for high-dose chemotherapy and in relapsed patients as salvage therapy [19-21]. The advantage of lenalidomide in POEMS patients could be the double nature of tumoricidal and antiangiogenic effects with ability to affect both cytokine production and plasmacellular disorder. After six lenalidomide cycles, our patient achieved a hematologic PR with persistence of monoclonal IgA by immunofixation, and normal VEGF level after eight cycles. We stopped lenalidomide in order to treat persistently PET-active bone lesions with radiotherapy. Three months after radiotherapy, we resumed lenalidomide at the dose of 25 mg per day on the basis of increasing VEGF levels. This data confirms the opportunity to continue lenalidomide as maintenance until relapse or toxicity as in MM. After 10 months, lenalidomide showed a low-toxicity profile without dose reduction or delay. We do not know the duration of response after transplant in POEMS, but relapses are described. Lenalidomide could be a good therapeutic option as consolidation-maintenance after transplant in responding patients, also considering data showing a significant prolongation of progression–free survival with lenalidomide maintenance after aPBSCT in MM pts [29, 30, 22]. Based on our experience, the use of lenalidomide plus dexamethasone seems to be the best choice for unfit POEMS patients relapsing after aPBSCT. Its use should be continued till relapse or toxicity, monitoring VEGF levels. Barbara Vannata*, Luca Laurenti*, Patrizia Chiusolo*, Federica Sorà*, Mario Balducci , Mario Sabatelli , Marco Luigetti , Claudia Giannotta§, Valerio De Stefano*, Giuseppe Leone*, Simona Sica*, * Department of Hematology, Catholic University of the Sacred Heart, Rome, Italy, Department of Radiotherapy, Catholic University of the Sacred Heart, Rome, Italy, Department of Neurology Catholic University of the Sacred Heart, Rome, Italy, § Department of Translational Medicine, Milan University, 2nd Neurology, IRCCS Humanitas Institute, Rozzano, Milan, Italy.