Poems Syndrome - frequently asked questions

Frequently asked questions about POEMS syndrome



(last revised 4 November 2017. Please contact Harry Ide at harryide6@gmail.com with questions, suggestions, and corrections!)

question: What causes POEMS?
question: What causes the plasma cell proliferative disorder in POEMS?
question: Is POEMS cancer?

question: How rare is POEMS?

question: Do I have POEMS? (How is it diagnosed?)
question: What tests are done for POEMS?

question: How is POEMS treated?
question: What should I know about autologous stem cell transplants?

question: How long do POEMS patients survive?
question: Will I relapse?

question: Where can I get more information about POEMS?

bibliography



QUESTION: What causes POEMS?

Technically, POEMS is paraneoplastic, caused by a plasma cell proliferative disorder. Here's what that means.[1]

When someone gets sick, her body may produce antibodies to help fight off the infection. Antibodies are produced by plasma cells. Each plasma cell produces just one kind of antibody; if your body needs more of that antibody, the plasma cell multiplies itself, so your body has more plasma cells making more of that antibody. Usually, you have many different kinds of plasma cells reacting to an infection, each producing different antibodies, which work more or less well. (In fact, your body even systematically mutates plasma cells to produce new antibodies that work better.) And when the infection is over, the plasma cells are supposed to stop multiplying. But sometimes, one clone of plasma cells reproduces more than it should. That's a monoclonal plasma cell proliferative disorder.

The antibody the monoclonal plasma cells produce is called an M-protein (short for monoclonal protein). Each antibody consists of two identical heavy chains, and two identical light chains. Heavy chains fall into one of five classes: IgA, IgD, IgE, IgG, and IgM; light chains are either lambda (λ) or kappa (κ). So, monoclonal proteins are identified by the classes of their heavy and light chains. More than 95% of POEMS M-proteins have lambda light chains. POEMS M-proteins are usually IgG or IgA, but may also be IgM. In one study, 44 POEMS patients had IgA lambda m-proteins, 40 had IgG lambda, and 1 had IgM lambda.

Sometimes (for example, in multiple myeloma), the monoclonal plasma cells basically take over the bone marrow, crowding out the other cells that bone marrow produces. Sometimes (for example, in light chain deposition disorder), the m-protein accumulates in different organs, causing them to malfunction. But POEMS is more complex. (This is the "paraneoplastic" part.) Cytokines are chemicals your cells use to communicate with each other--like hormones, but produced all around the body, and not just at one place. In POEMS, your body starts producing different amounts of cytokines than it normally would, and the cytokines (probably) cause the problems characteristic of POEMS.

We know that VEGF (vascular endothelial growth factor) is high in POEMS. Other abnormal cytokine levels have also been reported in POEMS, but they either are not as consistently elevated as VEGF, or have been tested rarely. For example, pro-inflammatory cytokines, including IL-6, TNF-alpha, and IL-1 beta, are often (but not always) high in POEMS.[2]

It is possible that other causes might produce similar symptoms--anything that causes similar levels of cytokines could result in similar symptoms. Dispenzieri now recognizes a Castleman variant of POEMS, which has many of the same symptoms but doesn't show any evidence of a monoclonal plasma cell proliferative disorder. Perhaps the Castleman variant of POEMS has a different cause.[31] But at least most cases of POEMS are caused by a monoclonal plasma cell proliferative disorder.[32]

We now have evidence that the monoclonal plasma cells in bone marrow produce VEGF. But in POEMS, bone marrow usually includes not only monoclonal plasma cells, but also increased numbers of polyclonal plasma cells. Strikingly, one study found that VEGF is also produced by the polyclonal plasma cells. The authors speculate that the monoclonal cells may cause the polyclonal increase, perhaps by producing IL-6. This may help explain why POEMS symptoms can be so severe even with a small monoclonal population: the small monoclonal population produces cytokines that cause damage, but also cause a larger increase in polyclonal plasma cells, which also produce the cytokines that cause the damage. This is still speculative; more work remains to be done here.[27]



QUESTION: What causes the plasma cell proliferative disorder in POEMS?

The monoclonal plasma cells reproduce when they shouldn't because of mutations. Mutations are changes in DNA, which encodes the instructions for making and running your body. Mutations may have no effect at all—but they can also cause many problems, including POEMS.

We know more about the mutations in multiple myeloma (another monoclonal plasma cell proliferative disorder) than about the mutations in POEMS. A recent review of multiple myeloma summarizes the mutations in this way:

"[A]pproximately 40% of multiple myeloma is characterized by the presence of trisomies in the neoplastic plasma cells (trisomic multiple myeloma), while most of the rest have a translocation involving the immunoglobulin heavy chain (IgH) locus on chromosome 14q32 (IgH translocated multiple myeloma). A small proportion of patients have both trisomies and IgH translocations. Trisomies and IgH translocations are considered primary cytogenetic abnormalities and occur at the time of establishment of MGUS. In addition, other cytogenetic changes termed secondary cytogenetic abnormalities arise along the disease course of multiple myeloma, including gain(1q), del(1p), del(17p), del(13), RAS mutations, and secondary translocations involving MYC."[33]

Here's what some of that terminology means. DNA is organized into chromosomes. You have two copies of each of your 23 chromosomes, one from your mother, and the other from your father. When one of your cells reproduces, it copies the DNA. The chromosomes are supposed to pair up; one pair of each goes to the new cell, and one pair stays in the old cell. But sometimes they don't pair up correctly. Trisomy is when one cell gets three ("tri") copies of a chromosome; monosomy is when one cell gets only one ("mono") copy of a chromosome. Translocations are when part of a chromosome moves to a different spot. Each chromosome has a short arm (named 'p', from the French petit, small), and a long arm (named 'q'). 'Gain' and 'del[etion]' mean what they seem to‐for example, 'gain(1q)' means that the cell has an extra copy of the long arm of chromosome 1. Special stains leave the chromosomes banded; '14q32', for example, refers to chromosome 14, long arm 'q', band 3, sub-band 2.

So, one set of mutations causes MGUS—that's the m-protein, without symptoms ("monoclonal gammopathy of undetermined significance"). Then another mutation, added to that, causes the switch from MGUS to multiple myeloma. Perhaps that's true of POEMS also.

Some of the same mutations have been reported in POEMS as in multiple myeloma–for example, translocations of the gene for the heavy chain of antibodies, found at chromosome 14q32. But the mutations aren't exactly the same, and (as in multiple myeloma) different patients have different mutations.[35] (For more information about your mutations, look in your bone marrow aspiration and biopsy report for the cytogenetics and FISH reports.)

What causes the mutations? We don't know, and it might be different in different cases. (Think about lung cancer—as is commonly known, lung cancer causes smoking, but about 20% of cases of lung cancer have other causes.) Any given mutation is either inherited, caused by environmental factors, or caused by DNA copy errors; all are possible.

(Yes, DNA copy errors might be the cause. Every time a cell reproduces, it has to copy its DNA. The copying mechanism in our cells is accurate, but not perfect. One group has even argued that two-thirds of the mutations in human cancers are caused by DNA copy errors.[34])



QUESTION: Is POEMS cancer?

Some physicians tell patients that POEMS is cancer; some say it is not. Who is right? Everyone! Cancer isn't a single disease; it's a cluster of related diseases. Whether POEMS counts as a cancer depends on how close a relation you insist on.

For example, POEMS does involve abnormal cell growth (like more standard cancers). But the cells don't grow indefinitely; for reasons we don't know, the growth is usually very limited (not like more standard cancers). (The median of plasma cells in bone marrow is less than 5%, for example.) And the damage is caused not by directly by the abnormal growth, but indirectly, by cytokines caused by the abnormal cells (or by normal cells acting abnormally because of cytokines produced by the abnormal cells) (again, not like more standard cancers). (See What causes POEMS? above for details.) So, POEMS is like more standard cancers in some ways, and not in others.



QUESTION: How rare is POEMS?

In 2003, about three in one million people in Japan had POEMS.[3]



QUESTION: Do I have POEMS? (How is it diagnosed?)

POEMS is a syndrome, which means that it's defined by symptoms. Different causes may result in similar symptoms. So, diagnosing POEMS is complex; it requires looking for patterns of symptoms and test results.[4]

Unfortunately, the name 'POEMS' is misleading. It's an acronym that stands for Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, and Skin changes. The article that proposed it in 1980 didn't propose those as diagnostic criteria, and discussed other equally important symptoms--and we've learned a lot about POEMS since then. So, you shouldn't think about p-o-e-m-s as determining whether you have POEMS syndrome.[5]

Instead, the most commonly used criteria for diagnosing POEMS require meeting four conditions:[6]

(A) peripheral neuropathy
the neuropathy is usually roughly equal on both sides of the body, starts earlier in (and is worse in) lower extremities than in upper extremities, and starts far away from the center of the body, and moves toward the center
(B) monoclonal plasma cell proliferative disorder
(C) EITHER Castleman disease OR sclerotic bone lesions OR elevated VEGF
(D) EITHER organomegaly OR extravascular volume overload OR endocrinopathy OR skin changes OR papilledema OR thrombocytosis/polycythemia

Whether these are the right criteria is controversial. Sometimes, for example, people meet all the other conditions, but don't have an m-protein, or even don't have neuropathy. One proposed revision has three major criteria--peripheral neuropathy, monoclonal plasma cell proliferative disorder, and elevated VEGF, with the rest being minor criteria. They require meeting all three major criteria, and one minor criterion, for definite POEMS, and meeting two of the three major criteria and one minor criterion for probable POEMS.[7]



QUESTION: What tests are done for POEMS?

Because POEMS has many different effects, many tests might be relevant. Here are a few that are especially important for diagnosing POEMS.[8]

--VEGF

VEGF (vascular endothelial growth factor) is usually high when POEMS is active; it's the single best test we have for POEMS (although it's not perfect). VEGF causes new blood vessels to grow ("angiogenesis"), and makes blood vessels leaky ("increases vascular permeability").

And it probably also is part of the cause of at least some POEMS symptoms. For example, it probably explains why POEMS patients often have problems with fluid leaking where it shouldn't, causing (among other problems) swollen ankles and legs. It may also help explain the neuropathy that's characteristic of POEMS, since VEGF can reduce the barrier between blood vessels and nerves, which may let something in that damages the nerves. And it may explain other problems characteristic of POEMS, too.[9]

VEGF can be measured either in serum or plasma. Serum VEGF is 10 to 50 times higher than plasma VEGF, because serum VEGF includes the VEGF in platelets, and plasma VEGF doesn't. (POEMS patients' platelets have a lot of VEGF in them, and POEMS often involves increased numbers of platelets too.) Whichever your physician is measuring, is fine--we know both are useful in diagnosing and following POEMS; what's controversial is which one is better. (Unfortunately, lab reports frequently don't mention whether the VEGF was measured in serum or in plasma.)[10]

VEGF is very useful for diagnosing POEMS. Plasma VEGF of at least 200 pg/mL has a specificity of 95% and a sensitivity of 68% for POEMS. (That is, 95% of people with plasma VEGF that high had POEMS, and 68% of POEMS patients had plasma VEGF that high.) And serum VEGF of at least 1920 pg/mL has a specificity of 97.6%, and a sensitivity of 73.3%, for POEMS. (That is, 97.6% of people with serum VEGF that high had POEMS, and 73.3% of POEMS patients had serum VEGF that high.)[11]

VEGF is also very useful for following POEMS after treatment. For following POEMS activity after treatment, the trend matters more than the actual value. And VEGF does go up and down for reasons that don't have anything to do with POEMS--so a single higher VEGF doesn't automatically imply that more treatment is required. [12]

If possible, always use the same lab, and have your blood drawn at the same place. One POEMS patient has had just one out-of-range VEGF after an autologous stem cell transplant, which occurred when he had his blood drawn at a different place. Differences in the way the blood sample is processed, as well as differences in the way the test is run, may affect results.

--for neuropathy

Besides a careful physical examination, POEMS patients need to have an EMG/NCS (electromyelogram / nerve conduction study), to characterize their neuropathy. EMG/NCS can help distinguish POEMS from other diseases--in particular, from CIDP (which POEMS patients are often misdiagnosed as having). For example, a terminal latency index ≥ 0.38 in the median nerve makes a diagnosis of POEMS more likely than a diagnosis of CIDP.[13]

--for monoclonal plasma cell proliferative disorder

Because the M-protein in POEMS is typically very small, it can be hard to find.

One blood test is serum protein electrophoresis (SPEP), but only about a quarter to half of POEMS patients have an m-protein on SPEP. Immunofixation is a more sensitive test. But even adding them together, and testing both blood and urine, doesn't find an M-protein in all POEMS patients.[14]

Bone marrow biopsies are very useful. In one study, two thirds of POEMS bone marrow biopsies showed a monoclonal plasma cell population (sometimes hard to find, because other plasma cells are also increased). (Flow cytometry is less sensitive than immunohistochemistry or in situ hybridization.) Usually, plasma cells make up a relatively small part of bone marrow cells in POEMS; the median in POEMS patients is less than 5% (though they can be a much higher percentage). Besides that, megakaryocytes--the cells that produce platelets--were increased in about half of the bone marrow biopsies, and clustered together in almost three-quarters of them; many of them also appeared abnormal. And many of the bone marrows showed lymphoid aggregates, usually rimmed with plasma cells.[15]

Another blood test that can be useful is serum free light chains. Because more light chains are made than heavy chains, a monoclonal plasma cell proliferative disorder will result in light chains that aren't attached to heavy chains--those are called "free light chains". But measuring free light chains in serum (blood) is less useful in POEMS than (for example) in multiple myeloma, because in addition to the monoclonal light chain, other light chains are elevated in POEMS. That's probably partly because the kidneys are removing light chains more slowly because of kidney damage, and partly because POEMS patients are producing more polyclonal antibodies too, for example, in the spleen, which is often enlarged.[16]

Finally, in some cases, biopsies of a skeletal lesion may find monoclonal plasma cells.

--for bone lesions

A CAT scan (CT) is the best way to find smaller lesions. PET scans (18-FDG PET-CT) are very helpful with larger lesions, but miss smaller lesions. Bone scans (scintigraphy) may find some lesions that CT misses. (Very little evidence is available about MRI, but MRI may help, for example, distinguish problematic lesions from benign bone islands.)

Skeletal surveys, on the other hand, miss a lot of bone lesions. In one study, CT found bone lesions in all 24 patients, while skeletal survey found lesions in only 15, and missed many lesions in those 15.[17]



QUESTION: How is POEMS treated?

The good news is that effective treatments for POEMS are available. Sometimes they're amazingly effective. One article in a medical journal is called 'Making the lame walk?', and another talks about a 'Lazarus-like response' to treatment! Not everyone improves that much, but being optimistic, and working hard to maximize your improvement, is completely justified. [18]

For patients who have three or fewer skeletal lesions, and do not have bone marrow involvement, radiation alone may be enough. Other patients will need a systemic therapy.[19]

One systemic therapy is an autologous stem cell transplant. This involves collecting hematopoietic stem cells from your blood, giving you high-dose chemotherapy, which kills off your bone marrow, and returning the stem cells to you. POEMS patients improve after this, but it is an intense procedure, which is not appropriate for everyone. Between a quarter and half of POEMS patients experience something like peritransplant engraftment syndrome (fever, weight gain, skin rash, diarrhea, respiratory symptoms); this can be treated effectively by short courses of high-dose corticosteroids. Some evidence suggests that using cyclophosphamide (Cytoxan) or lenalidomide (Revlimid) before the transplant may reduce the number of patients who experience peritransplant engraftment syndrome.[20]

Other chemotherapies are available. For example, one prospective study found that low-dose melphalan (Alkeran) and prednisone is very effective. Cyclophosphamide (Cytoxan) also helps a significant percentage of POEMS patients.[21]

Thalidomide, and its derivative lenalidomide (Revlimid), are effective. Many physicians have avoided using thalidomide, because it can cause neuropathy. A trial ("JPOST") recently concluded that thalidomide-dexamethasone does reduce VEGF, and that the side effects--in particular, sinus bradycardia and sensory neuropathy--were relatively mild and manageable. This is the first placebo-controlled, double-blind, study of a POEMS treatment.[22]

A new class of drugs called "proteasome inhibitors" has been used for POEMS. Very few cases have been published, but they suggest that bortezomib (Velcade) is effective for POEMS. However, it can also cause neuropathy. In one study of 20 patients, using a low dose of bortezomib (Velcade) (1 mg/m^2), in conjunction with cyclophosphamide (Cytoxan) and dexamethasone, 7 of 17 evaluable patients reached complete hematologic response, 19 of 20 patients improved neurologically, and none worsened neurologically. (Median follow-up was 11 months.) [23]

A trial of another proteasome inhibitor, ixazomib citrate (Ninlaro), together with lenalidomide (Revlimid) and dexamethasone, is currently underway at Mayo-Rochester. (ClinicalTrials trial NCT02921893). They are currently recruiting POEMS patients who need treatment (whether they have been treated before or not), whose VEGF is more than twice the upper limit of normal. See the link (or contact them) for more details.

Because VEGF is usually high in POEMS, and probably causes at least some POEMS symptoms, using a drug that directly reduces VEGF seems appealing. However, bevacizumab (Avastin), which does that, appears to be dangerous--while some POEMS patients treated with bevacizumab (along with other therapies) have improved, others have died. One study found that while bevacizumab reduces VEGF, it doesn't reduce hepatocyte growth factor, which also makes blood vessels leaky; perhaps it (or other cytokines VEGF doesn't affect) is responsible for the deaths.[24]



QUESTION: What should I know about autologous stem cell transplants?

In an autologous stem cell transplant, you get medicine to cause your bone marrow to make more stem cells and release them into your blood ("mobilization"), the stem cells are removed by a process called apheresis ("collection"), you're given a high dose of chemotherapy (usually melphalan (Alkeran)), and the stem cells are put back. They then migrate to the bone marrow and begin producing white blood cells, red blood cells, and platelets ("engraftment").

We know that autologous stem cell transplant is an effective treatment for POEMS.[28]

Like all treatments, it has risks. One that's especially common in POEMS patients is often called 'engraftment syndrome' (or 'autologous graft-versus-host disease'). It involves fever, diarrhea, weight gain, rash, and breathing difficulty. About a third of POEMS patients experience this. Make sure your physicians know that in POEMS, it occurs at a different time in POEMS patients than in others--anywhere from 7 to 15 days after the stem cells are returned to your body. If you get a fever or have the other symptoms above, your physicians need to treat you for possible infections, but also need to give you steroids for possible engraftment syndrome (even if the symptoms do not occur at the normal time for engraftment). Although no studies have determined the best dose, Dispenzieri suggests starting with prednisone from 1-2 mg/kg and 500 mg, and staying on steroids at least 10 days. I strongly recommend making sure that your physicians have read the article that shows this (Dispenzieri, 2008, European journal of hematology, which is available free here--print a copy and give it to them!), and are prepared to give you steroids as well as antibiotics. Since POEMS is so rare, they may not know about the unusual timing.[29]



QUESTION: How long do POEMS patients survive?

Two large retrospective studies suggest that the current 10-year overall survival rate is about 78%. This is overall survival, and some of the people who died in those ten years did not die of POEMS. In one of the studies, 92 patients died; 17 (19%) of POEMS-related causes, 16 (17%) of causes unrelated to POEMS, and 59 (64%) of unknown causes. If the known causes of death are representative, POEMS patients are as likely to die of other problems as of POEMS. [26]

Two older articles gave median overall survival of 165 months (patients seen at Mayo from 1960 to 1998) and 147 months (137 POEMS patients seen at Mayo from 1975 to 2003). These underestimate current survival, at least partly because of improved treatments. That's clear from one of the more recent studies, which found that the ten-year overall survival rate was 55% for patients diagnosed before 2003, and 79% for patients diagnosed after 2003.[25]



QUESTION: Will I relapse?

Two recent studies have examined relapse/progression. Unfortunately, they don't reach exactly the same conclusions, at least partly because of differences in the patients and in the information they had available about the patients. But here are the results:[30]

Kourelis 2016a
low albumin at diagnosis made early death more likely
not achieving complete hematologic response (negative serum and urine immunofixation and negative bone marrow) was associated with worse progression-free survival
older patients were more likely to progress or relapse
Wang 2017
four factors were associated with worse overall survival:
   age > 50 years
   pulmonary hypertension
   pleural effusion
   estimated glomerular filtration rate < 30 ml/min/1.73 m^2

If you have those features, you're more likely to encounter problems.

Further treatment is likely to help. In one study, '92% of [79] patients responded to second-line therapy, and the 6 patients who were refractory to second-line treatment received third-line treatment (5 responded)' (Kourelis 2016 p.1083). Thirty patients had a second relapse/progression; two didn't respond to third-line treatment. And eight patients had a third relapse/progression; three didn't respond to fourth-line treatments.

In the end, the evidence clearly shows that POEMS patients need follow-up after treatment, and patients who are at higher risk for progression/relapse should be followed more closely. But it also indicates that most POEMS patients who relapse or progress will respond to further treatment. Kourelis 2016 concludes:

[P]atients with POEMS should undergo life-long follow-up as [relapse/progression] appears to be salvageable with second-line treatment. The results of this study suggest that closer follow-up is indicated during the first 5 years from diagnosis, that is, every 3-6 months, followed by every 6-12 months thereafter. Closer follow-up is also indicated in patients who have not achieved a hematologic [complete response] to first-line treatment. Routine PET and VEGF surveillance identifies subclinical disease activity and should be strongly considered in the long-term follow-up of these patients. Treatment should be initiated in all patients with a clinical [relapse/progression] and most patients with radiographic [relapse/progression], but observation is reasonable in patients with an isolated hematologic [relapse/progression].



QUESTION: Where can I get more information about POEMS?

One very good source is other patients! Two online communities provide very helpful information and advice.

     https://www.smartpatients.com/poems (click on "Join the conversation")
     Facebook

Some useful articles about POEMS are listed under 'more information' above, and studies you can participate (including treatment trials) are listed under 'studies' above.



Footnotes

[1] ^ two useful recent reviews of POEMS: Dispenzieri 2017, Li 2013; see also Dispenzieri 2003

[2] ^ some recent articles on POEMS cytokines: Keyzner 2013, Yamada 2013, Kanai 2012

[3] ^ Misawa 2013, citing Arimura 2007 (which I haven't been able to get a copy of)

[4] ^ For example, Dispenzieri 2017 pp.819-20 discusses a Castleman disease variant of POEMS, which lacks either peripheral neuropathy or an M-protein

[5] ^ Bardwick 1980

[6] ^ Dispenzieri 2007 (used, for example, in Dispenzieri 2017 and Li 2013)

[7] ^ Misawa 2013

[8] ^ Dispenzieri 2017 p.817 has a list of the minimum tests she recommends

[9] ^ Nasu 2012, Kanai 2012. See Watanabe 1998 and Scarlato 2005 for earlier discussion

[10] ^ Tokashiki 2003, Dispenzieri 2017, Hashiguchi-2000

[11] ^ D'Souza 2011 (plasma) and Wang 2014 (serum)

[12] ^ D'Souza 2011, D'Souza 2012, Goto 2008

[13] ^ Mauermann 2012, Nasu 2012. In Mauermann 2012, it had a specificity of 77% and a sensitivity of 70% in distinguishing POEMS from CIDP.

[14] In Dao 2011, 83 of 87 (95%) POEMS patients had an M-spike on SPEP or immunofixation.

[15] ^ Dao 2011

[16] ^ Stankowski-Drengler 2010, Wang 2014b

[17] ^ Glazebrook 2015

[18] ^ Chalk 2008, Patel 2008.

[19] ^ treatment generally: Kuwabara 2012; Dispenzieri 2012. radiation: Humeniiuk 2013.

[20] ^ D'Souza 2012 and Karam 2015

[21] ^ (low-dose) melphalan-dexamethasone: Li 2011

[22] ^ thalidomide (and JPOST trial): Misawa 2016; see Katayama 2015 and Misawa 2015 for background. lenalidomide: Zagouri 2014.

[23] ^ Zeng 2013. He 2017 is the study of reduced-dose bortezomib in 20 patients.

[24] ^ Yamada 2013

[25] ^ Dispenzieri 2003, Allam 2008. Kourelis 2016a has the pre- and post-2003 ten-year overall survival rates. All three studies are about patients seen at Mayo Clinic.

[26] ^ Kourelis 2016a studied 291 patients (diagnosed from 1974 to 2014), with a median follow-up of 76 months. 92 patients died in the study period; 17 (19%) of the deaths were POEMS-related, 16 (17%) were unrelated, and 59 (64%) were unknown. The 10-year overall survival rate was 62%; for patients diagnosed before 2003, it was 55%; for patients diagnosed after 2003, 79%. Wang 2017 studied 362 patients (seen from 2000 to 2015) with a median follow-up of 30 months. 44 patients died in the study period, of progression-related renal failure (14), cardiopulmonary failure (5), disease progression not further specified (14), infection (6), unknown (5) (44 of 362 patients). The 5-year overall survival was 84%, and the 10-year overall-survival was 77% (p.102). In the high-risk group, the 5-year overall survival was 63%, and in the low-risk group, 95%.

[27] ^ Wang 2016c. See Dao 2011 for earlier evidence of the polyclonal expansion.

[28] ^ D'Souza 2012 (supplemented by Karam 2015 and Chandrashekaran 2015), Cook 2016.

[29] ^ Dispenzieri 2008. For the recommended dose, see Dispenzieri 2017 p.822.

[30] ^ Kourelis 2016a, Wang 2017 (partly validated by Kourelis 2017).

[31] ^ Castleman disease characteristically involves high levels of IL-6. Some cases of Castleman are associated with a virus called ‘HHV-8', whose genome encodes a homolog of human IL-6—it's not identical to human IL-6, but it's functionally similar. That's why Sylvant (siltuximab) is only approved for HHV-8-negative Castleman disease—it won't bind to the viral IL-6 produced by HHV8. Could a virus also cause some cases of POEMS-like symptoms?

[32] ^ Key evidence that at least most cases of POEMS are caused by a monoclonal plasma cell proliferative disorder:
(a) Treatments aimed at the problematic plasma cell clone are effective.
(b) In the published reports of the M-protein in POEMS, the m-protein is either IgLV 1-40 or IgLV 1-44. Why the light chain is always one of those two groups is unclear, but if the m-protein didn't cause POEMS, it's hard to imagine that the light chains would be restricted in that way. (This isn't the whole story--there are some kappa light chain cases of POEMS, which won't be IgLV. The largest study (Li 2012 Annals of hematology) found that in 30 POEMS patients all the light chains were either from IGLV 1-40 (11 patients, 37%) or IGLV 1-44 (19, 63%). The three other studies (all cited in Li 2012) include 27 patients total. One meeting abstract documented restriction to IGLV 1-40 or 1-44 in 14 of 17 patients; the abstract doesn’t say what they found in the other three, and the article hasn’t ever been published–see Aravamudan Blood 2008 112 p.2744.)

[33] ^ Rajkumar, 2016, American Journal of Hematology pp.722-723; see tables II and III for details.

[34] ^ See Tomasetti, 2017, Science, and Tomasetti, Science, 2015. Their arguments are indirect, and I don’t know how to evaluate them. But it is clear that DNA copy errors are at least a possible cause of mutations in cancer.



[35] ^ Three articles discuss the mutations in POEMS.
(a) Bryce 2008 American Journal of Hematology found that in 37 patients: 14 (38%) showed monosomy 13; 1 had trisomy 3 and 7; 3 had IgH translocation t(11;14)(q13;q32). They conclude, ‘The monosomy 13 is in line with other plasma cell disorders while the low prevalence of hyperdiploidy and abnormalities at 14q32 is unique.’
(b) Kang 2008 American Journal of Hematology found that in 20 patients, 15% had t(4;14) and 25% had t(11;14), for a total of 45% showing 14q32 translocations. 5 25% had deletions of 13q14, 20% had amplification of 1q21.
(c) Rose 1997 Leukemia found that in 6 patients, one patient had trisomy 9, one had trisomy 11.



Bibliography
(Links are to the abstracts in PubMed, where they are available.)
Allam 2008
Allam JS, Kennedy CC, Aksamit TR, and Dispenzieri A. 'Pulmonary manifestations in patients with POEMS syndrome: a retrospective review of 137 patients.' Chest 2008 Apr; 133(4): 969-74.
Arimura 2007
Arimura K, Hashiguchi T. 'Crow-Fukase syndrome: clinical features, pathogenesis and treatment in Japan'. In Current topics in neuroimmunology. Edited by Yamamura T, Kira J, Tabira T. Bologna Italy: Medimond, 2007: 241-245.
Bardwick 1980
Bardwick PA, Zvaifler NJ, Gill GN, Newman D, Greenway GD, Resnick DL. '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 (Baltimore) 1980 Jul;59(4):311-22.
Chalk 2008
Chalk C. 'Making the lame walk?: transplantation for POEMS.' Neurology 2008 Nov 18;71(21):1658-9. doi: 10.1212/01.wnl.0000326574.37138.35.
Chandrashekaran 2015
Chandrashekaran S, Dispenzieri A, Cha SS, Kennedy CC. 'Pulmonary morbidity improves after autologous stem cell transplantation in POEMS syndrome'. Respiratory Medicine 2015 Jan;109(1):122-30. doi: 10.1016/j.rmed.2014.11.005.
Cook 2016
Cook G, Iacobelli S, van Biezen A, Ziagkos D, LeBlond V, Abraham J, McQuaker G, Schoenland S, Rambaldi A, Halaburda K, Rovira M, Sica S, Byrne J, Garcia Sanz R, Nagler A, van de Donk NW, Sinisalo M, Cook M, Kröger N, De Witte T, Morris C, Garderet L. 'High dose therapy and autologous stem cell transplantation in patients with POEMS syndrome: A retrospective study of the Plasma Cell Disorder sub-committee of the Chronic Malignancy Working Party of the European Society for Blood & Marrow Transplantation'. Haematologica 2017 Jan;102(1):160-167. doi: 10.3324/haematol.2016.148460.
D'Souza 2011
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Dao 2011
Dao LN, Hanson CA, Dispenzieri A, Morice WG, Kurtin PJ, Hoyer JD. 'Bone marrow histopathology in POEMS syndrome: a distinctive combination of plasma cell, lymphoid, and myeloid findings in 87 patients.' Blood 2011 Jun 16;117(24):6438-44. doi: 10.1182/blood-2010-11-316935.
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Dispenzieri A, Kyle RA, Lacy MQ, Rajkumar SV, Therneau TM, Larson DR, Greipp PR,Witzig TE, Basu R, Suarez GA, Fonseca R, Lust JA, Gertz MA. 'POEMS syndrome: definitions and long-term outcome.' Blood 2003 Apr 1;101(7):2496-506.
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Dispenzieri A. 'How I treat POEMS syndrome.' Blood 2012 Jun 14;119(24):5650-8. doi: 10.1182/blood-2012-03-378992.
Dispenzieri 2017
Dispenzieri A. 'POEMS syndrome: 2017 update on diagnosis, risk-stratification, and management.' American journal of hematology 2017 Aug;92(8):814-829. doi: 10.1002/ajh.24802.
Glazebrook 2015
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Goto H, Nishio M, Kumano K, Fujimoto K, Yamaguchi K, Koike T. 'Discrepancy between disease activity and levels of vascular endothelial growth factor in a patient with POEMS syndrome successfully treated with autologous stem-cell transplantation. Bone Marrow Transplant 2008 Nov;42(9):627-9. doi: 10.1038/bmt.2008.223.
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He 2017
He Haiyan, Weijun Fu, Du Juan, Jiang Hua, Hou Jian. 'Successful treatment of newly diagnosed POEMS syndrome with reduced-dose bortezomib based regimen'. British journal of haematology [pre-print] (January 2017)
Humeniuk 2013
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Kanai 2012
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Katayama 2015
Katayama K, Misawa S, Sato Y, Sobue G, Yabe I, Watanabe O, Nishizawa M, Kusunoki S, Kikuchi S, Nakashima I, Ikeda S, Kohara N, Kanda T, Kira J, Hanaoka H, Kuwabara S. 'Japanese POEMS syndrome with Thalidomide (J-POST) Trial: study protocol for a phase II/III multicentre, randomised, double-blind, placebo-controlled trial'. BMJ Open 2015 Jan 8;5(1):e007330. doi: 10.1136/bmjopen-2014-007330.
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Kuwabara S, Dispenzieri A, Arimura K, Misawa S, Nakaseko C. 'Treatment for POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome.' Cochrane Database Syst Rev 2012 Jun 13;6:CD006828. doi: 10.1002/14651858.CD006828.pub3.
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