POEMS: Rare, Often Misdiagnosed and Disabling if Not Properly Treated

Early recognition is key to effective management

Megakaryocytic hyperplasia and clustering reminiscent of myeloproliferative neoplasms can be seen in the bone marrow trephines of POEMS patients (H&E, 400x).

POEMS (i.e., polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) is a rare and disabling plasma cell disorder that is commonly misdiagnosed as chronic inflammatory demyelinating polyneuropathy (CIDP). Treatment of the two pathologies differs, so early recognition is key.

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Also called osteosclerotic myeloma, Crow-Fukase syndrome or Takatsuki syndrome, POEMS is characterized primarily by peripheral neuropathy and the presence of a monoclonal protein, sclerotic bone lesions, elevated vascular endothelial growth factor and Castleman disease. Other signs and symptoms include extravascular volume overload, organomegaly, endocrinopathy, vascular skin changes, papilledema, polycythemia and thrombocytosis.

The condition is thought to arise from a cytokine imbalance precipitated by an excessive production of multiple proinflammatory and angiogenic cytokines, with concurrent suppression of anti-inflammatory cytokines.

According to one Japanese study, the prevalence of POEMS is about 0.3 per 100,000 population.

“Many clinicians — even specialists — are unfamiliar with POEMS because it’s so rare. However, there are many signs and symptoms that must be considered when arriving at a proper diagnosis,” says Cleveland Clinic hematologist/oncologist Jack Khouri, MD, who specializes in rare plasma cell disorders within the Rare Cancers and Blood Diseases program.

Dr. Khouri was the lead author of a review of the syndrome, published recently in JAMA Oncology.

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Diagnosis necessitates monoclonal plasma workup

Patients with POEMS typically present with longstanding and progressively worsening peripheral neuropathy that is length-dependent and demyelinating. While the syndrome is similar to the more common CIDP, there are several important differences. Axonal degeneration, neuropathic pain and lower-limb atrophy are more prominent in POEMS than in CIDP, while cranial nerve involvement and dysautonomia are far less common in patients with POEMS.  

“When you encounter a patient with peripheral neuropathy that seems a little unusual or dissimilar to what you usually see, a workup for monoclonal plasma cell disorders is strongly advised,” Dr. Khouri says, adding that the diagnosis is typically made by hematologists and neurologists working in tandem.

The workup includes neurophysiologic studies, paraprotein testing, radiography, fundoscopy and an endocrine and cardiopulmonary evaluation. Electromyography and nerve conduction studies are required to characterize the neuropathy.

Autologous hematopoietic cell transplant offers best chance for recovery

The treatment of POEMS is aimed at eradicating the culprit plasma cell clone, much as in cases of multiple myeloma. High-dose melphalan followed by autologous hematopoietic cell transplant (HCT) offers the best long-term outcomes for eligible patients. “Patients need to be able to tolerate the treatment. If they can, HCT done early in the disease course provides the highest chance for remission,” Dr. Khouri says.

In the largest series to date, of 59 patients with POEMS who underwent HCT, more than 90% responded to treatment, and 5-year progression-free survival was 75%. In Dr. Khouri’s experience, patients who undergo HCT typically experience 5 to 10 years of remission and continued improvement in symptoms without the need for medications.

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Plasma cell-directed therapy is implemented for patients who cannot tolerate HCT. This includes immunomodulatory drugs such as lenalidomide, proteasome inhibitors such as bortezomib, dexamethasone and cyclophosphamide in different combinations. Radiation therapy can also be used in select cases. The anti-CD38 monoclonal antibody daratumumab is currently under study.

In studies, a combination of lenalidomide and dexamethasone typically produces rapid relief, with 75% to 90% of patients symptom-free by 3 years. Relief from the neuropathy and associated skin, eye, liver and endocrine problems can begin as quickly as 2 months, but the neuropathy can take much longer to resolve completely. “We tell patients not to be discouraged. Nerves need time to regenerate,” Dr. Khouri points out. In particular, muscle strength and gait typically improve steadily, while foot drop can take longer to resolve.

Reduced serologic markers and clinical improvements indicate when treatment can be stopped, but patients need to be carefully monitored for signs of relapse. Since POEMS is such a heterogenous condition, every patient’s clinical course varies. But, Dr. Khouri emphasizes, “People really do get better…as long as they have the right diagnosis.”