Durable Responses with Autologous Hematopoietic Stem Cell Transplantation (Auto-HCT) in Patients with POEMS Syndrome

POEMS syndrome, also known as osteosclerotic myeloma, is a constellation of polyneuropathy, monoclonal plasma cell proliferative disorder and several other clinical features.^{1, 2} The 3 major diagnostic criteria include Castleman disease, sclerotic bone lesions and elevated serum levels of vascular endothelial growth factor (VEGF). The rest of the acronym, i.e organomegaly, endocrinopathy and skin changes, form the minor criteria along with extravascular volume overload, papilledema and thrombocytosis/polycythemia. Diagnosis of POEMS syndrome depends on the presence of polyneuropathy, monoclonal gammopathy and one other major and one minor criteria³.

Treatment is aimed at eradicating the underlying plasma cell clone and the control of major symptoms. In cases of 1-3 plasmacytomas without bone marrow infiltration, localized radiation therapy may be sufficient⁴. Conversely, widespread disease requires systemic therapy, which is adopted largely from therapy for multiple myeloma⁴. Due to its rarity, current literature for POEMS syndrome comprises case reports and series, and no randomized trials have been conducted⁵. In 2001, the first report of a successful auto-HCT in a patient with POEMS syndrome was published⁶, followed by similar case series from different centers^7-9. Results suggest that high-dose chemotherapy and auto-HCT is associated with durable clinical response, but significant post-transplant morbidity^7-9. Here we present our experience in 7 patients with POEMS syndrome who underwent auto-HCT at the MD Anderson Cancer Center (MDACC).

Diagnosis of POEMS was confirmed according to the criteria of Dispenzieri et. al.³ Peripheral blood stem cells were collected with granulocyte colony-stimulating factor (G-CSF) in 6 patients, and with cyclophosphamide and G-CSF in 1 patient. The preparative regimen was melphalan 200 mg/m² in 6 patients, while 1 patient received melphalan 180 mg/m² due to renal insufficiency. Patients were evaluated for responses (hematologic, radiologic and clinical), toxicity, progression-free survival (PFS) and overall survival (OS). Hematologic response was defined by the International Myeloma Working Group (IMWG) criteria¹⁰. Radiologic data for bone lesions was assessed with bone surveys and PET/CT scans. Improvement of clinical symptoms was defined by amelioration in performance status, laboratory values and physical examination findings. Toxicities were defined per the Common Terminology Criteria for Adverse Events version 4.0 (CTCAEv4.0).

As described in table 1, all 7 patients had osteosclerotic bone lesions, monoclonal gammopathy and polyneuropathy. 3 patients had biopsy-proven Castleman disease. Other features were: skin involvement in 3 (1 with Raynaud's, 1 with suspected plethora, 1 with hyperpigmentation and scleroderma like thickening), endocrinopathy with hypogonadism in 3, ascites in 2, anasarca in 2, pulmonary hypertension in 1, papilledema in 1, pseudotumor cerebri in 2, and pericardial effusion in 1. Three patients had thrombocytosis which normalized after treatment. An adequate number of peripheral blood stem cells (PBSC) were collected in all patients (median 4.93×10⁶/kg; range 2.4-7.37×10⁶/kg). All patients received systemic therapy prior to auto-HCT; 3 patients underwent localized radiation for bone disease. Median follow up after auto-HCT was 30 months (10 –83 months). Median time to both neutrophil and platelet engraftment was 11 days. Only 1 (14%) patient had engraftment syndrome, consisting of a maculopapular skin rash involving 85% of the body surface area on day 10 after auto-ASCT, which resolved within 48 hours of application of triamcinolone cream. Significant post auto-HCT complications were fungal pneumonia in 2 patients and pulmonary embolism in 1. Patients fully recovered from these complications. One-year transplant-related mortality (TRM) was 0%. Hematologic responses were measured 3, 6 and 12 months after auto-HSCT and then every 4-6 months. Best responses were achieved at 3-6 months: 3 patients (43%) had a complete response, 3 (43%) had a very good partial response, and 1 (14%) had a partial response by IMWG criteria. All 7 patients had complete or significant resolution of their clinical symptoms after auto-HCT: 4 had significant improvement in neuropathy, 1 had significant improvement in fever and night sweats, and 6 had stable sclerotic bone lesions while 1 had mild improvement. Organomegaly normalized in both patients who had it, while 4 patients with anasarca, ascites, skin disease or papilledema had complete resolution of their problems. Median Karnofsky performance status improved from 80% (70–100) at the time of transplant to 90% (80–100) by one year post auto-HCT. Estimated 1 and 5-year PFS/OS were 100%/100% and 86%/100%; 1 patient relapsed 3 years after auto-HSCT. Six patients are alive with controlled disease, while 1 patient died 6 years after auto-HCT due to gastrointestinal bleeding unrelated to his POEMS.

Table 1. Patient and transplantation characteristics (n=7).

Median age at diagnosis	45 (39-56)
Median age at transplant	47 (39-58)
Time to transplantation from diagnosis (months)	16.5 (5.5-88.5)
Sex: male/female	6/1
Karnofsky Performance Status at baseline	80 (70-100%)
Monoclonal gammopathy	7 (100%)
Polyneuropathy	7 (100%)
Organomegaly	2 (29%)
Endocrinopathy	4 (57%) Hypogonadism 3 Hypopitutrism 1
Skin changes	3 (43%)
Extravascular fluid overload	5 (71%)
Castleman disease	3 (43%)
Osteosclerotic bone lesions	7 (100%)
Ig heavy chain
IgA	3 (43%)
IgG	4 (57%)
IgM	0
Ig light chain
Lambda	5 (71%)
Kappa	2 (29%)
BM involvement by monoclonal plasma cells	7 (<5% in all)
Induction treatment
Cyclophosphamide based	3
Melphalan based	1
IMID	2
Bortezomib	3
Mean number of regimens	2
Radiotherapy	3 (43%)

Abbreviations: BM = bone marrow; IMID = immunomodulatory drug

The natural history of POEMS syndrome is defined by progressive polyneuropathy and sclerotic bone disease which leads to significant morbidity, along with mortality if respiratory compromise ensues¹¹. Both conventional and novel therapies such as melphalan, dexamethasone, cyclophosphamide, lenalidomide, and bortezomib, as single agents and in combination, lead to objective responses^12-14. Previous reports have described prolonged remission rates and significant improvement of clinical symptoms for POEMS after HD melphalan and auto-HCT^7-9. Our retrospective case series indicates a 100% response rate with 3 CR, 3 VGPR and 1 PR, without significant auto-HCT-related morbidity or mortality. Importantly, a complete hematologic response was not required for significant clinical response.

We were able to mobilize > 2 × 10⁶ CD34+ PBSC from all 7 patients, with only 1 patient requiring a combination of chemotherapy and growth factors. This is consistent with data from Mayo clinic⁸, but contrary to some reports which documented poor mobilization in these patients^{15, 16}. With small numbers and a heterogeneous population, it is difficult to comment on the causes of this discrepancy.

The response rates and durable PFS and OS were similar to previous reports of HD melphalan and auto-HCT. This favorable outcome may be attributed to a relatively younger patient population (median age 45) and a lower disease burden at auto-HCT, since all patients had received induction therapy.

This case series of 7 patients enhances the prior limited number of POEMS patients described in the literature who have successfully undergone auto-HCT which has led to improved objective hematologic response, decrease in significant symptoms and recovery of functional status. Further studies are needed to investigate the role of proteasome inhibitors and IMIDs with or without auto-HCT.