POEMS Syndrome

POEMS Syndrome Describe the clinical features, laboratory investigations and treatment of POEMS syndrome. (15 marks)

Definition. POEMS syndrome is a rare multisystem paraneoplastic disorder caused by an underlying clonal plasma cell disorder. The acronym stands for Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy and Skin changes. It is also called osteosclerotic myeloma, Crow–Fukase syndrome or Takatsuki syndrome.

The acronym is incomplete and misleading. It omits several of the most useful diagnostic features, which are captured by the second acronym PEST — Papilloedema, Extravascular volume overload, Sclerotic bone lesions, and Thrombocytosis/erythrocytosis. Candidates who quote only POEMS lose the features that actually make the diagnosis.

Central pathogenic mechanism. A small, almost always lambda-restricted clonal plasma cell population drives markedly elevated vascular endothelial growth factor (VEGF). VEGF increases vascular permeability and angiogenesis, and explains most of the clinical picture — oedema, effusions, organomegaly, papilloedema, skin haemangiomata and neuropathy. Other cytokines (IL-1, IL-6, TNF-alpha) contribute.

Why it matters in geriatric practice. Median age at presentation is around 50, but a substantial minority present in the sixties and seventies. The diagnosis must be considered in what would otherwise be called a monoclonal gammopathy of undetermined significance when unusual features appear — peripheral neuropathy, thrombocytosis and extracellular volume overload. In an older patient the neuropathy is routinely blamed on diabetes, alcohol, B12 deficiency or ageing, and the oedema on heart failure — which is why diagnosis is so often delayed by years.

P — Polyneuropathy (present in essentially 100%; it is the dominant symptom). A chronic, symmetrical, ascending, distal, sensorimotor polyneuropathy. It begins with tingling, numbness and coldness of the feet, then progresses to severe motor weakness that may confine the patient to a wheelchair. It is predominantly demyelinating with axonal loss, and is painful in only a minority — a useful clue, since it is otherwise easily mistaken for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).

O — Organomegaly. Hepatomegaly, splenomegaly and lymphadenopathy. Enlarged nodes may show Castleman disease on biopsy — a recognised and important association.

E — Endocrinopathy. Present in about two-thirds. The commonest are hypogonadism (erectile dysfunction, gynaecomastia, amenorrhoea), then hypothyroidism, diabetes mellitus, and adrenal insufficiency. Hypogonadism is the most frequent single endocrine abnormality. Diabetes and hypothyroidism alone are too common in the elderly to count towards diagnosis.

M — Monoclonal plasma cell disorder. Almost invariably IgG or IgA with a lambda light chain. The M-protein is characteristically small and may be missed on routine electrophoresis — immunofixation of serum and urine is mandatory.

S — Skin changes. Hyperpigmentation (commonest), haemangiomata and glomeruloid angiomata (highly characteristic), hypertrichosis, acrocyanosis and plethora, white nails, sclerodermatous thickening and clubbing.

P — Papilloedema. Present in about one-third. It is often asymptomatic, so fundoscopy must be performed in every suspected case; its presence strongly supports the diagnosis.

E — Extravascular volume overload. Peripheral oedema, ascites, and pleural or pericardial effusions. In an older patient this is almost always first attributed to heart failure, nephrotic syndrome or liver disease, and the true diagnosis emerges only when these are excluded.

S — Sclerotic bone lesions. Present in about 95% and virtually diagnostic in this clinical context. They may be purely sclerotic, or sclerotic-rimmed lucencies with a "soap-bubble" appearance. They are frequently missed because a bone scan is normal and a skeletal survey is often reported as unremarkable — dedicated CT or PET-CT is needed.

T — Thrombocytosis and erythrocytosis. Thrombocytosis occurs in about half. This is a critical negative discriminator: anaemia and thrombocytopenia point to multiple myeloma or amyloidosis, not POEMS.

Other features and the major hazard. Pulmonary hypertension, restrictive lung disease, reduced DLCO, weight loss, fatigue, clubbing and a hypercoagulable state. Arterial and venous thrombotic events — stroke, myocardial infarction, peripheral arterial occlusion — occur in roughly 10–20% and are a leading cause of death, an especially important consideration in older patients who already have vascular risk factors.

Polyneuropathy — typically 3. Castleman disease Organomegaly (spleen, liver, lymph nodes) demyelinating 4. Sclerotic bone lesions Extravascular volume overload (oedema,

Elevated VEGF effusion, ascites)

Monoclonal plasma cell proliferative Endocrinopathy (adrenal, thyroid, pituitary, disorder — almost always lambda gonadal, parathyroid, pancreatic) — excluding diabetes and hypothyroidism alone Skin changes Papilloedema Thrombocytosis or polycythaemia Laboratory Investigations Category Test Expected finding / purpose Plasma cell clone Serum and 24-hour urine protein Small IgG or IgA lambda M-protein. Marrow electrophoresis with immunofixation; serum usually shows <5–10% clonal plasma cells. The free light chain assay; bone marrow aspirate free light chain ratio is frequently normal and and trephine with immunohistochemistry and therefore uninformative — a recognised pitfall flow cytometry The key biomarker Serum or plasma VEGF Markedly elevated — usually more than three to four times the upper limit of normal. It is the single most useful diagnostic test and also the best marker for monitoring response. Serum values run higher than plasma values, so use the same medium throughout follow-up Neurological Nerve conduction studies and EMG; CSF Demyelinating pattern with axonal loss, more examination; sural nerve biopsy if needed marked in the lower limbs, with less temporal dispersion and less conduction block than CIDP. CSF shows albuminocytological dissociation — raised protein with normal cell count Skeletal imaging Whole-body low-dose CT or FDG PET-CT. Plain Sclerotic or mixed sclerotic-lucent lesions, skeletal survey only if CT is unavailable commonly in spine, pelvis and ribs. A bone scan is typically normal and does not exclude the diagnosis Haematology Complete blood count Thrombocytosis and/or erythrocytosis.

Step 1 — Decide whether the disease is localised or disseminated. This single decision determines the entire treatment plan and depends on whether the marrow contains clonal plasma cells and how many bone lesions are present.

Localised disease — one to three sclerotic bone lesions with no clonal plasma cells in the marrow. Treat with radiotherapy, 40–50 Gy to the lesion. Response is slow, taking 3–6 months or longer, but is achieved in the majority, and roughly half are cured by radiotherapy alone. Surgical excision is an alternative for a solitary accessible lesion.

Disseminated disease — the transplant-eligible patient. High-dose melphalan with autologous stem cell transplantation is the treatment of choice and remains the favoured therapy on the basis of case series, producing durable remissions even without maintenance therapy. Typical outcomes are a complete haematological response in about 60% and a complete VEGF response in about 50%, with 5-year progression-free survival around 75% and 5-year overall survival around 90%. Induction with a few cycles before transplant is often given.

Disseminated disease — the transplant-ineligible or older patient. Options are lenalidomide with dexamethasone, melphalan with dexamethasone, or a bortezomib-based regimen. In a phase 2 trial of 12 cycles of lenalidomide and dexamethasone in 41 patients, the complete haematological response rate was 46%, the neurological response rate 95% and the VEGF response rate 83%, with estimated 3-year overall survival of 90% and progression-free survival of 75%. Lenalidomide and dexamethasone is therefore the practical first choice in an older, frail or transplant-ineligible patient, with thromboprophylaxis mandatory.

Supportive care is not optional — it determines function. Intensive physiotherapy and occupational therapy, ankle-foot orthoses and gait aids, falls prevention (this neuropathy is a major falls risk in an older patient), neuropathic pain management, diuretics for volume overload, hormone replacement for the identified endocrinopathy, and thromboprophylaxis given the recognised hypercoagulable state. Steroids and IVIG do not work in POEMS — persisting with them wastes months.

Monitoring and prognosis. Follow VEGF, the M-protein, neurological function (ONLS or similar score), and volume status. Neurological recovery lags months behind the haematological and VEGF response, so patients must be counselled not to expect early improvement in walking. Prognosis has transformed: median survival was under 3 years in early series and 10-year overall survival now exceeds 50–60%, even before the availability of monoclonal antibodies, bispecific T-cell engagers and CAR-T. Adverse prognostic factors are age over 50, pulmonary hypertension, effusions, low albumin and reduced eGFR.