Case report Successful treatment of POEMS syndrome with ... - Nature

Bone Marrow Transplantation (2001) 28, 305–309  2001 Nature Publishing Group All rights reserved 0268–3369/01 $15.00 www.nature.com/bmt

Case report Successful treatment of POEMS syndrome with autologous hematopoietic progenitor cell transplantation WJ Hogan1, MQ Lacy1, GA Wiseman2, RD Fealey3, A Dispenzieri1 and MA Gertz1 1

Division of Hematology and Internal Medicine, 2Section of Nuclear Medicine, and 3Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA

Summary: POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) is a plasma cell dyscrasia that differs substantially from classic multiple myeloma. It is often associated with disabling polyneuropathy in younger patients. Current therapeutic approaches are frequently inadequate and leave many patients wheelchair-bound with significant deterioration in quality and length of life. We present the case of a young man with progressive disease despite conventional therapeutic approaches. We describe a novel approach to treatment with a boneseeking radiopharmaceutical, samarium-153 ethylene diamine tetramethylene phosphonate (153Sm-EDTMP), followed by myeloablative chemotherapy with autologous hematopoietic progenitor cell reconstitution. This approach resulted in regression of the organomegaly and skin changes and in neurologic improvement both clinically and electrophysiologically. The patient progressed from being wheelchair-bound to independent ambulation. An aggressive approach should be considered in patients with POEMS syndrome in whom standard therapeutic measures fail. Bone Marrow Transplantation (2001) 28, 305–309. Keywords: POEMS syndrome; autologous hematopoietic stem cell transplantation; samarium-153 EDTMP

The association between polyneuropathy and monoclonal proteins has been recognized for many years. The acronym POEMS was coined by Bardwick et al1 to describe a syndrome of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. This syndrome occurs more frequently in Japan, where it is commonly known as Crow–Fukase syndrome.2 In a recent review at the Mayo Clinic, only 20 of 93 patients had the complete pentad. A constellation of additional features has been described, including fever, peripheral edema (29%), ascites (11%), pleural effusion, polycythemia, pulmonary hyperCorrespondence: Dr MQ Lacy, Division of Hematology and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA Received 18 January 2001; accepted 30 April 2001

tension, papilledema (37%), and thrombocytosis.3 The polyneuropathy associated with POEMS is characterized by mixed sensorimotor changes. Organomegaly usually presents as hepatosplenomegaly and lymphadenopathy, revealing angiofollicular hyperplasia pathologically. Gonadal dysfunction, glucose intolerance, hyperprolactinemia, and hypothyroidism have all been described in the spectrum of endocrinopathies. Hyperpigmentation, plethora, scleroderma-like thickening, hypertrichosis, clubbing, and Raynaud’s phenomenon characterize skin changes.4 Monoclonal gammopathy is present in the majority of patients, with IgG (41%) and IgA (39%) heavy chains predominating, and almost invariably, lambda light chains. POEMS is usually associated with osteosclerotic myeloma, in which patients tend to be younger (median age 51 vs 64 years) and rarely have symptoms of typical myeloma such as bone pain, anemia, hypercalcemia, or renal insufficiency. Their prognosis is better, with an estimated 5-year survival of 60%,3 and death is almost always related to causes other than multiple myeloma. The etiology and pathophysiology of POEMS syndrome are currently under intense investigation. It is hypothesized that the syndrome may be mediated by aberrant cytokine or angiogenic factor activity. Elevated serum levels of IL6 and IL-1␤ have been reported by some investigators, and it has been proposed that levels of IL-6 correlate with disease activity.5 Soubrier et al6 have shown that patients with POEMS syndrome have higher levels of TNF-␣ and IL-6 than patients with classic multiple myeloma. Chronically elevated TNF-␣ levels have been associated with inflammatory demyelinating neuropathy, organomegaly affecting liver and spleen, endocrine dysfunction, and skin changes such as hypertrichosis.7 Vascular endothelial growth factor (VEGF) serum levels have been shown to be markedly elevated in patients with POEMS,6,8 and correlate with disease activity. It has been postulated that cytokines or VEGF secreted both from plasma cells and from macrophages in the sclerotic bone lesions may be responsible for inducing the disease manifestations. Traditional therapeutic approaches have included local radiotherapy, prednisone, melphalan/prednisone, plasmapheresis, and intravenous immunoglobulin. These have been used with variable success, with 57% of patients having some response and 11% having stable disease. The combination of melphalan and 153Sm-EDTMP has

Treatment of POEMS syndrome WJ Hogan et al

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been previously evaluated in patients with multiple myeloma. In an abstract submitted to the American Society of Hematology 2000,19 a phase 1 study of nine patients was presented. The protocol included treatment with a fixed dose of melphalan (200 mg/m2) and dose escalation of the 153 Sm-EDTMP. Dose levels were 6, 12, and 19.8 mCi/kg (ideal body weight). Peripheral blood stem cells were reinfused when 3.6 mCi or less of 153Sm-EDTMP remained in the patient. Preliminary results for early toxicity were available on nine patients. At each dose level, the average dose to the red marrow was 6.57, 11.68, and 18.08 Gy, respectively. Other than myelosuppression, no significant toxicity was associated with the 153Sm-EDTMP, and no dose-limiting toxicity was observed. Case report A 41-year-old man presented to another institution in April 1996 with progressive neurologic dysfunction. He related the onset of his symptoms to strenuous activity, after which he experienced low back pain. This continued for several days before paresthesias developed in both feet. Over the next couple of weeks, the pain dissipated, but the level of sensory changes progressively ascended, accompanied by weakness in the distal lower extremities and erectile dysfunction. There was no prior history of exposure to neurologic toxins and no family history of neuropathy. Physical examination revealed a sensorimotor neuropathy, and electromyography (EMG) showed changes suggestive of demyelination. The patient underwent five courses of plasma exchange without benefit. Further evaluation revealed a serum monoclonal IgG␭ protein of 0.44 g/dl, and the patient was treated with a 4-day cycle of melphalan and prednisone. After one cycle there was stabilization, but after the second cycle it became clear that the neuropathy had worsened. He went on to develop a profound, predominantly motor neuropathy affecting the lower extremities more than the upper, and presented to our institution in September 1996 for further evaluation. The iliopsoas muscles had only antigravity strength, and with virtually no movement in the lower extremity muscles the patient became wheelchair-dependent. Significant weakness of the hands also developed, making it impossible for him to open packages. Sensory disturbance was noted to the mid-calf and in the fingertips and was associated with burning dysesthesias. Muscle tone was decreased, reflexes were absent in the legs, and EMG revealed dysfunction of large-fiber more than small-fiber sensory modalities. General examination revealed hepatomegaly (liver 4 cm below the right costal margin) and hyperpigmentation of the skin, particularly of the nose and lower extremities. Laboratory testing included cerebrospinal fluid examination, which revealed a protein level ⬎200 mg/dl (normal ⬍35). Endocrine parameters are given in Table 1. Serum protein electrophoresis and immunofixation results are outlined in Table 2. Testosterone and vitamin B12 replacement was given. No antibodies were detected with specificity for defined neural antigens. Skeletal survey revealed a single small lytic lesion with a slightly sclerotic rim on the right side of the T10 vertebral body. Computed tomography-

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guided biopsy revealed a plasmacytoma, and bone marrow examination showed a polyclonal plasma cell staining pattern with 2% plasma cells, a ␬:␭ ratio of 1:1, and a labeling index of 0%. The patient received radiotherapy, 45 Gy, to the T10 vertebral body which dramatically improved the neuropathy. Over the ensuing months, he progressed from being wheelchair-bound to walking with a walker, then with crutches, and subsequently with a cane. The hyperpigmentation was unchanged, and the monoclonal protein remained detectable in the serum. In 1998, he noted gradual worsening of lower extremity weakness, returning hand weakness, worsening erectile dysfunction, and increased hyperpigmentation. A skeletal survey in June 1998 revealed lytic lesions in the cervical spine, seventh rib, and scapula, with mixed lytic and sclerotic changes in the manubrium and the T10 vertebral body lesion (Figure 1). Bone marrow biopsy revealed polyclonal plasma cells. Radiotherapy – 45 Gy to the cervical spine, 45 Gy to the left shoulder, 50 Gy to the sternum, and 50 Gy to the right ribs – brought no improvement. Four cycles of therapy with doxorubicin and dexamethasone (without vincristine because of the neuropathy) resulted in a decrease of the M-protein level from 0.5 to 0.25 mg/dl. In January 1999, a repeat bone survey showed multiple new lesions in the spine, pelvis, and femur. Examination revealed cushingoid facies, diffuse hyperpigmentation, and a liver palpable 8 cm below the right costal margin. Neurologic examination revealed upper and lower extremity weakness with bilateral foot drop and gait ataxia requiring crutches for ambulation and bilateral foot braces. EMG showed distinct worsening of the evoked compound muscle and sensory nerve action potential amplitudes of the upper extremities and no responses in the lower extremities. Overall findings indicated a severe generalized sensorimotor axonal and demyelinating polyradiculoneuropathy. In view of the severity of the disease and the patient’s deteriorating quality of life, he was offered the option of high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation. Hematopoietic progenitor cell collection was performed by using cyclophosphamide, 3 g/m2, given as two divided doses of 1.5 g/m2 on consecutive days, followed by granulocyte–macrophage colony-stimulating factor, 500 ␮g subcutaneously daily for 8 days. A total of 5.84 × 106 CD34+ cells/kg were obtained by apheresis over 3 consecutive days. A radioisotope bone scan demonstrated uptake in the neoplastic lesions, and therefore the patient was deemed suitable for 153SmEDTMP therapy (Figure 2). He received a total dose of 111 MBq/kg, and follow-up whole body counts were performed to determine when the residual radioactivity was low enough to permit stem cell infusion. Moderate cytopenias developed (hemoglobin 9.6 g/dl, white blood cells 1.7 × 109/l, absolute neutrophil count (ANC) 1.2 × 109/l, platelets 44 × 109/l). Sixteen days after administration of 153SmEDTMP, whole-body radiation measurements showed 237 ␮Ci of remaining 153Sm-EDTMP. It was considered safe to proceed with high-dose melphalan conditioning (initiated 20 days after 153Sm-EDTMP) and stem cell infusion. He received melphalan 100 mg/m2 on 2 consecutive days as an outpatient and peripheral blood stem cells were infused 2 days later. His subsequent hospital course was complicated


Table 1

307

Endocrine parameters

sTSH Free T4 Testosterone Free testosterone Corticotropin AM cortisol

0.3–5.0 mIU/l 0.8–1.8 ng/dl 240–950 ng/dl 9–30 ng/dl ⬍23 pg/ml 7–25

Sept 1996

June 1998

Jan 1999

Feb 2001

3.2

6.6 1.0 165 3.0 24 12

6.6 0.7

3.5

236

sTSH = serum thyroid-stimulating hormone; T4 = thyroxine. Table 2

Electrophoresis and immunofixation results Sept 1996

Serum Electrophoresis Immunoelectrophoresis Urine Immunoelectrophoresis

M-peak = 0.73 g/dl

June 1998

Jan 1999

M-peak = 0.93 g/dl

M-peak = 0.94 g/dl

Monoclonal IgG␭

Monoclonal IgG␭

Monoclonal ␭ plus IgG fragment

Monoclonal ␭

Mar 2000 12 months post transplant

M-peak too small to quantify Monoclonal IgG␭

No monoclonal protein detected

Feb 2001 23 months post transplant

M-peak not detected No monoclonal protein detected Not performed

Figure 1 Skeletal survey revealing mixed lytic and sclerotic changes (arrows) in the T10 vertebral body (A) and the manubrium (B), with lytic lesions in the scapula (C).

by postural hypotension, pruritus, mild glucose intolerance, mucositis requiring central parenteral nutrition, and culturenegative neutropenic fever requiring hospitalization for 6 days. Neutrophil recovery (⬎500 × 106/l) occurred on day +13 and platelet recovery (⬎50 × 109/l) on day +14. The hepatomegaly resolved during the week after transplantation, and neurologic function gradually improved. Six months after transplantation, he had marked improvement in the strength and mobility of his proximal lower extremities. Bilateral foot drop and mild paresthesias in the hands persisted. EMG showed mild improvement from the pretransplantation EMG (Table 3). A skeletal survey showed no new lesions. The patient progressively improved in ambulation until he could walk independently. Clinical benefit was still evident at last follow-up 23 months post transplant, with stable neurologic function, resolution of subclinical hypothyroidism, and disappearance of the serum and urine monoclonal protein (Table 2).

Discussion Current therapeutic approaches for POEMS syndrome reportedly provide benefit in 57% of patients and disease stabilization in another 11%. Because it is a rare syndrome, most current chemotherapeutic approaches are based on traditional therapy for multiple myeloma, with omission of neurotoxic agents such as vincristine. Plasma exchange and intravenous gamma globulin are frequently employed for symptomatic polyneuropathy, but are often inadequate. In patients with a solitary plasmacytoma, external-beam radiation therapy with or without surgical excision may lead to regression of the neuropathy for years. This observation supports the hypothesis that POEMS is a paraneoplastic phenomenon mediated by soluble factors produced by abnormal plasma cells. We postulate that systemic approaches with chemotherapeutic or radiopharmaceutical agents are required to achieve remission when plasma cells Bone Marrow Transplantation


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Figure 2 Radioisotope bone scan demonstrating uptake and therefore making the patient a suitable candidate for samarium-153 EDTMP therapy.

Table 3

Electromyographic findings from before (1/99) and 6 months after transplantation (9/99) Amplitude 1/99

9/99

Ref

0.0 0 1.3 2

0.0 3 1.7 3

⬎4 ⬎15 ⬎6 ⬎10

Nerve conduction studies Median motor Median sensory Ulnar motor Ulnar sensory

Spontaneous fibrillations

Voluntary motor unit potential studies Biceps brachii First dorsal interosseous Triceps Tensor fascia lata Tibialis anterior Vastus medialis Thoracic paraspinal

1/99

9/99

+/− +++ 0 0 ND ++ 0

+/− +++ 0 +/− +++ ++ +

Distal latencya

Velocity 1/99

29

Reduced recruitment 1/99

9/99

+++ ND ++

+ ++ +

9/99

35

Ref

⬎51

Duration (long) 1/99

+ ND ++

9/99

++ + ++ ND ++ +

F-wave latencyb

1/99

9/99

Ref

1/99

9/99

NR NR 4.1 3.5

NR 3.8 3.9 3.4

⬍3.8 ⬍3.6 ⬍3.1

70.7

52.4

Amplitude (high)c 1/99

9/99

+ + ++

+/− + + ++ ++ ++ +

Amplitude (low) 1/99

9/99

Phases

1/99

9/99

25% 100%

+ ND ++

Ref

+ +

ND 100%

100% 75%

a

Distal latency measures conduction time of the distal part of the nerve; lower values are better. F-wave latency measures conduction time of the proximal part of a nerve; lower values are better. c Amplitude of motor unit potential increases when nerves regenerate, a favorable finding. ND = not done. b

are not confined to an isolated area, and high-dose therapy with stem cell rescue may be more effective than traditional doses of chemotherapy at achieving this goal. The radiopharmaceutical 153Sm-EDTMP is a potent short-range ␤ particle-emitting radioisotope (153Sm) conjugated to a bone-seeking chelate (EDTMP). The 153SmBone Marrow Transplantation

EDTMP becomes deposited on the surface of trabecular and cortical bone, and less than 2% of its activity is retained in non-osseous tissue 3 h after administration,9 with complete urinary excretion 6 h after injection.10 It has a relatively short half-life (46.7 h) and has been studied extensively for the treatment of painful osseous metastasis.10,11


It has been found effective in this setting, with temporary myelosuppression as the main toxicity. Turner and colleagues12 reported results with 153Sm-EDTMP and melphalan in murine myeloma. They found that median survival after treatment with nonmyeloablative doses of 153 Sm-EDTMP (29 days) and melphalan (31 days) was significantly prolonged, compared with untreated mice (23 days). Syngeneic bone marrow transplantation after myeloablative doses of 153Sm-EDTMP with melphalan was even more effective (42 days). There was no evidence of radiotoxicity in nonhematopoietic organs. This approach permits specific bone marrow ablation with minimal nonhematopoietic toxicity. It may be suitable for patients who cannot be treated with standard total-body irradiation because of extensive prior external-beam radiation therapy. Given the severity of the disease in our patient and the fact that he no longer responded to standard therapy, a novel therapeutic approach was required. There is preliminary evidence to suggest that autologous hematopoietic progenitor cell transplantation may benefit patients with other low-grade dysproteinemias.13–15 Many investigators have shown that high-dose melphalan followed by hematopoietic stem cell reconstitution results in reversal of amyloid deposition syndromes in two-thirds of patients surviving at 1 year.16 This therapeutic approach was offered to our patient because it has been shown to have benefit in multiple myeloma, with a mortality risk of less than 2%.17,18 He has had a favorable response, with dramatic regression of the organomegaly and skin changes and a significant decrease in the monoclonal protein. The neuropathy continues to improve clinically and by electromyography. An aggressive approach should be considered in patients with POEMS syndrome who fail to respond to standard therapeutic measures. This is likely to provide maximal benefit if it is begun before permanent loss of neurologic function. References 1 Bardwick PA, Zvaifler NJ, Gill GN et al. Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes: the POEMS syndrome. Report on two cases and a review of the literature. Medicine (Balt) 1980; 59: 311–322. 2 Nakanishi T, Sobue I, Toyokura Y et al. The Crow–Fukase syndrome: a study of 102 cases in Japan. Neurology 1984; 34: 712–720. 3 Miralles GD, O’Fallon JR, Talley NJ. Plasma-cell dyscrasia with polyneuropathy. The spectrum of POEMS syndrome. New Engl J Med 1992; 327: 1919–1923. 4 Lee GR, Foerster J, Lukens J et al. Wintrobe’s Clinical Hematology, tenth edn, vol. 2. Williams & Wilkins: Baltimore, 1999. 5 Hitoshi S, Suzuki K, Sakuta M. Elevated serum interleukin-6 in POEMS syndrome reflects the activity of the disease. Intern Med 1994; 33: 583–587.

6 Soubrier M, Dubost JJ, Serre AF et al. Growth factors in POEMS syndrome: evidence for a marked increase in circulating vascular endothelial growth factor. Arthr Rheum 1997; 40: 786–787. 7 Gherardi RK, Belec L, Soubrier M et al. Overproduction of proinflammatory cytokines imbalanced by their antagonists in POEMS syndrome. Blood 1996; 87: 1458–1465. 8 Watanabe O, Arimura K, Kitajima I et al. Greatly raised vascular endothelial growth factor (VEGF) in POEMS syndrome (letter). Lancet 1996; 347: 702. 9 McEwan AJ. Unsealed source therapy of painful bone metastases: an update. Semin Nucl Med 1997; 27: 165–182. 10 Ahonen A, Joensuu H, Hiltunen J et al. Samarium-153EDTMP in bone metastases. J Nucl Biol Med 1994; 38: 123–127. 11 Tian JH, Zhang JM, Hou QT et al. Multicentre trial on the efficacy and toxicity of single-dose samarium-153-ethylene diamine tetramethylene phosphonate as a palliative treatment for painful skeletal metastases in China. Eur J Nucl Med 1999; 26: 2–7. 12 Turner JH, Claringbold PG, Manning LS et al. Radiopharmaceutical therapy of 5T33 murine myeloma by sequential treatment with samarium-153 ethylenediaminetetramethylene phosphonate, melphalan, and bone marrow transplantation. J Natl Cancer Inst 1993; 85: 1508–1513. 13 Comenzo RL, Vosburgh E, Falk RH et al. Dose-intensive melphalan with blood stem-cell support for the treatment of AL (amyloid light-chain) amyloidosis: survival and responses in 25 patients. Blood 1998; 91: 3662–3670. 14 Moreau P, Milpied N, de Faucal P et al. High-dose melphalan and autologous bone marrow transplantation for systemic AL amyloidosis with cardiac involvement (letter). Blood 1996; 87: 3063–3064. 15 van Buren M, Hene RJ, Verdonck LF et al. Clinical remission after syngeneic bone marrow transplantation in a patient with AL amyloidosis. Ann Intern Med 1995; 122: 508–510. 16 Comenzo RL. American Society of Hematology Education Program Book. High-Dose Therapy for the Treatment of Primary Systemic Amyloidosis. American Society of Hematology: New Orleans, 1999, pp 347–357. 17 Gertz MA, Lacy MQ, Inwards DJ et al. Early harvest and late transplantation as an effective therapeutic strategy in multiple myeloma. Bone Marrow Transplant 1999; 23: 221–226. 18 Alegre A, Diaz-Mediavilla J, San-Miguel J et al. Autologous peripheral blood stem cell transplantation for multiple myeloma: a report of 259 cases from the Spanish Registry. Spanish Registry for Transplant in MM (Grupo Espanol de Trasplante Hematopoyetico-GETH) and PETHEMA. Bone Marrow Transplant 1998; 21: 133–140.

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Reference added in proof 19 Turner JH, Claringbold PG, Manning LS, O’Donoghue HL, Berger JD, Glancy RJ. Radiopharmaceutical therapy of 5T33 murine myeloma by sequential treatment with samarium-153 ethylenediaminetetramethylene phosphonate, melphalan, and bone marrow transplantation. J Natl Cancer Inst 1993; 15: 1508–1513.

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