High-dose therapy and autologous blood stem cell transplantation in POEMS syndrome

Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a multisystem disorder initially described by Japanese authors1 and then reported in Europe and North America.2-4 It is characterized by the combination of conditions that make up its abbreviation and may also include systemic symptoms, edema and anasarca, thrombocytosis, and various other manifestations.1-4 

This syndrome is associated with a plasma cell dyscrasia having some unique features such as osteosclerotic bone lesions and λ-light chain isotype of secreted monoclonal immunoglobulin (MIg).1-4The pathogenesis of POEMS syndrome is still unknown, but all symptoms are likely secondary to the plasma cell proliferation as supported by the dramatic improvement that may be obtained by radiotherapy and/or surgical excision in patients with solitary plasmocytoma and by the reappearance of POEMS symptoms when bone lesions recur.5,6 

In patients with diffuse bone marrow infiltration or multifocal lesions, conventional chemotherapy is usually proposed, but patient's quality of life most often deteriorates because of progressive neuropathy.7,8 Because of the well-established dose-response effect of melphalan in myeloma patients,9 we explored high-dose therapy (HDT) and stem cell rescue as an alternative approach in 5 patients.

Diagnosis of POEMS syndrome was considered in patients who presented with plasma cell proliferation associated with peripheral neuropathy, in the absence of any known cause of nerve involvement. All patients with multifocal bone lesions or diffuse bone marrow plasmatic infiltration were offered the option of HDT followed by autologous transplantation.

Since 1996, 5 patients (of 9 patients with POEMS) fulfilled these criteria. All gave informed consent and received HDT. They were between 44 and 62 years of age. Table 1 lists the main elements of POEMS in each patient. Monoclonal IgAλ and IgGλ were detected in the serum of 3 and 1 patients, respectively. The last patient had a biclonal IgMλ and IgGκ gammopathy. In all cases, the monoclonal component was small, below 10 g/L, and polyclonal immunoglobulin level was normal. One patient (case 3) had nephrotic syndrome, and renal biopsy showed glomerular alterations, including cellular proliferation and mesangiolysis that suggested POEMS nephropathy10,11; congo red staining was negative.

Three patients had multiple bone lesions that were purely osteosclerotic and mixed, osteosclerotic and osteolytic, in 1 and 2 cases, respectively. In these patients, standard bone marrow examinations were normal, and the plasmacytic nature of the bone lesions was proven by a focal biopsy. One patient (case 5) presented with solitary mixed iliac plasmocytoma and has diffuse bone marrow infiltration by monotypic plasma cells bearing λ light chains. Patient 3 had no detectable bone lesion but diffuse bone marrow lymphoplasmacytic infiltration. Appropriate staining of biopsies did not detect AL amyloidosis in any case.

All patients had distal bilateral sensory disturbance predominating in the lower limbs, associated with abolition of deep tendon reflexes. Two patients also presented with motor deficiency, including one who was bedridden because of tetraparesia. Isolated increase in protein level (above 1 g/L) was detected in the cerebrospinal fluid of the 4 studied patients. Electromyographic studies provided evidence for demyelinating lesions in all patients either isolated (n = 2) or associated with axonal degeneration (n = 3).

Other manifestations of POEMS syndrome (Table 1) included organomegaly in 3 patients; impotence, diabetes mellitus, adrenal insufficiency, and/or hypothyroidism in 4 patients; skin changes in 4 patients (hyperpigmentation in 3, telangiectasia in 1); and peripheral edema in 3 patients, associated with papilledema in 2 cases. In all cases, blood cell counts were normal.

As indicated in Table 2, patient 1 was initially considered to have Guillain-Barré syndrome and progressively became bedridden despite various therapeutic attempts. Other patients had been briefly or not previously treated.

Patients were treated as follows: (1) Local radiation was considered in the patients who had a prominent focal bone lesion and was actually performed in 3 patients. (2) Autologous peripheral blood stem cell (PBSC) collection was performed after mobilization by chemotherapy (intravenous cyclophosphamide over 2 days, 60 mg/kg/d) plus subcutaneous granulocyte colony-stimulating factor (G-CSF, 5 μg/kg/d). (3) HDT and PBSC transplantations were performed about 1 month after PBSC collection according to the regimens listed in Table2.

All 5 patients in whom we planned to perform HDT actually received this treatment. No toxic deaths occurred during PBSC mobilization or transplantation. Posttransplant neutrophil and platelet recoveries (> 500 × 10⁶/L and > 50 × 10⁹/L, respectively) occurred within 15 days and were sustained in all cases. The morbidity of the procedure, including mucositis and culture-negative neutropenic fever for 2 to 6 days, was not unexpected in any case, including in the patient who received sequential HDT and tandem transplantation while bedridden. Thus, in contrast to AL amyloidosis,12,13 the unique features of POEMS syndrome, particularly osteosclerosis and neuropathy-related disability, may not translate into higher risk of HDT as compared with classic multiple myeloma.

After HDT, MIg was no longer detectable by immunofixation in the serum or urine of 4 patients. The other patient (case 3) achieved a very good response with disappearance of abnormal bone marrow infiltration and with normal serum electrophoresis, whereas the MIg was still detectable by serum immunofixation. In all patients, MIg was easily detectable before transplantation, and HDT likely played a crucial role in tumor mass reduction. The small number of patients precludes any definitive conclusion about the best high-dose therapeutic strategy (one or 2 HDT, with or without total body irradiation) to propose to patients with POEMS. In contrast, mobilizing PBSCs by growth factor alone might be more convenient than using high-dose cyclophosphamide, which potentially increases the risks of the procedure, whereas it did not produce significant tumor mass reduction in any of our patients, as assessed by follow-up of MIg level.

In all cases, remission of plasma cell proliferation was associated with a marked improvement in performance and in neurologic symptoms (Table 2). Motor deficiency significantly improved, particularly in the tetraplegic patient who could walk again about 4 months after transplantation. Similarly, sensory disturbance improved in all cases, allowing, for instance, patient 3 to jog a few kilometers, whereas ataxia precluded running even a few meters before HDT. In all cases but one (case 2), initially abolished deep tendon reflexes reappeared. Electromyographic studies were repeated only in patient 5, who initially had isolated demyelinating lesions, and showed posttransplantation normalization of nerve conduction speeds.

In addition to neurologic symptoms, other manifestations of the POEMS syndrome improved, especially skin changes, edema, papilledema, and organomegaly that was no longer detectable after transplantation in any case. Serum thyroid-stimulating hormone levels returned to normal value in the 2 patients with hypothyroidism, whereas the patient with adrenal insufficiency still needed low-dose hydrocortisone after transplantation. In the same patient, all symptoms related to POEMS nephropathy disappeared except hypertension. Within a median follow-up of 36 months since HDT, no patient experienced a relapse either of plasma cell dyscrasia or of related POEMS manifestations.

Although still poorly understood, the pathogenesis of the POEMS syndrome may be related to production by the clonal plasma cells (or their environment) of a combination of soluble factors, resulting in increased vascular permeability and neoangiogenesis.14,15Among various cytokines, vascular endothelial growth factor may have a pivotal role.16,17 We studied vascular endothelial growth factor serum levels in 2 patients (cases 1 and 2) by using an enzyme-linked immunosorbent assay adapted from Fixe et al.18 In both, pretreatment level was high (3684 and 2644 pg/mL, respectively, as compared with 471 (± 86) pg/mL in 37 healthy blood donors), and posttransplantation levels returned to normal (240 and 394 pg/mL 1 month after HDT, respectively).

Although involving a small number of patients, this retrospective study shows the interest of HDT with stem cell support in patients with POEMS syndrome who present with multifocal bone lesions and/or diffuse plasmacytic bone marrow infiltration. In patients with a limited number of solitary plasmocytomas, radiation therapy probably remains the treatment of choice, but HDT should be studied in larger studies as an alternative, particularly when complete remission, including disappearance of the MIg, is not achieved or when relapse occurs.