Index
- reviews
- diagnosis and symptoms
- a new test: serum P1NP
- a second new test: serum heavy/light chain assay
- serum VEGF
- serum free light chain ratio
- pleural effusions
- neuropathy
- monitoring for relapses
- imaging bone lesions
- treatment
- lenalidomide (Revlimid)
- autologous stem cell transplant
- bibliography
This is my summary of what we learned about POEMS syndrome from articles published in 2014. Please let me know about any mistakes I made, or about other articles with interesting results! Contact me at harryide6@gmail.com.
--Harry A Ide, 10 January 2015reviews
- Dispenzieri published another review this year (Dispenzieri 2014). (There are some copy editing problems with this article; if anything doesn't make sense, or if you have trouble finding the relevant references, see Dispenzieri 2012 or Li 2013.)
diagnosis, symptoms, and signs
a new test: serum P1NP
- Wang 2014a offers an interesting new test for POEMS.
- P1NP (N-terminal propeptide of type I collagen) is a marker of bone formation, which is especially interesting in POEMS because most POEMS patients have sclerotic lesions (that is, have areas in their bones that show up as bright white on x-rays because they are especially dense).
- They looked at serum total P1NP levels in 45 newly diagnosed POEMS patients, 28 healthy people, and in patients with other related diseases (18 with CIDP, 11 with Castleman disease, 15 with multiple myeloma, and 10 with primary light-chain amyloidosis).
- POEMS patients had higher levels of P1NP than the rest. The median for POEMS patients was 137 ng/mL (range 18-792); for healthy people, for example, the median was 35 ng/mL.
- The best cutoff was 70 ng/mL, which resulted in a specificity of 91.5% and a sensitivity of 80%--that is, 91.5% of people with serum P1NP of at least 70 ng/mL had POEMS, and 80% of POEMS patients had a serum P1NP that high.
- P1NP was as useful for diagnosis as serum VEGF.
- Perhaps surprisingly, patients who had bone lesions didn't have higher P1NP than patients who did not. They suggest that this may imply that patients without bone lesions had bone lesions that were undetectable given current technology. But they didn't say how they checked for bone lesions. (See Glazebrook 2014, which I discuss below, for more about imaging bone lesions.)
a second new test: serum heavy/light chain assay
- Wang 2014 reports the results of a new test, the serum heavy/light chain assay, from ten POEMS patients.
- Each antibody consists of heavy chains (IgA, IgG, IgM, IgD, or IgE) and light chains (lambda or kappa). The heavy/light chain assay gives the amount of antibodies with a combination of a heavy and a light chain (for example, IgA lambda).
- Almost all the POEMS patients had an abnormal heavy/light chain ratio:
| clone | lambda | kappa | ratio |
|---|---|---|---|
| IgA lambda | 80% high IgA lambda (median 1.81 g/L, range 1.17-9.89 g/L) |
20% low IgA kappa (median 0.84 g/L, range 0.37-1.23 g/L) |
80% abnormal IgA kappa/IgA lambda ratio (median 0.32, range 0.04-1.01) |
| IgG lambda | 80% high IgG lambda (median 6.68 g/L, range 2.94-20.3 g/L) |
20% low IgG kappa (median 6.34 g/L, range 3.57-9.6 g/L) |
100% abnormal IgG kappa/IgG lambda ratio (median 1.1, range 0.31-1.21) |
- Perhaps this will allow detection of monoclonal plasma cell proliferation at lower levels than the other currently available tests do.
- It will be interesting to see heavy/light chain assay results on POEMS patients who don't have M-proteins on serum or urine protein electrophoresis or immunofixation.
serum VEGF
what we knew before this article- Serum VEGF (like plasma VEGF) is useful in diagnosing and following up POEMS.
- Wang 2014a looked at serum VEGF in 45 POEMS patients, and found the best cutoff was 1920 pg/mL, which had a specificity of 97.6% and a sensitivity of 73.3%. (That is, 97.6% of people with serum VEGF that high had POEMS, and 73.3% of POEMS patients had serum VEGF that high.)
- (Compare D'Souza 2011's finding that a cut-off of 200 pg/mL for plasma VEGF had a specificity of 95% and a sensitivity of 68% for POEMS.)
- They also found that combining serum VEGF and serum P1NP into a single test (serum total P1NP > 70 ng/mL OR serum VEGF > 1920 pg/mL) resulted in a sensitivity of 91.1% and specificity of 90.2%
serum free light chain ratio
the puzzle: Stankowski-Drengler 2010 found 45 of 50 (90%) POEMS patients had elevated lambda free light chains, but only nine (18%) of them had an abnormal free light-chain ratio, and kappa free light chains were increased in 68% of the patients (all of whom had a monoclonal lambda plasma cell proliferative disorder). Similarly, Wang 2014 found 56 of 83 POEMS patients (67%) had elevated lambda serum free light chains, but only 11 (13%) had an abnormal serum free light chain ratio. If the problematic plasma cell clone is producing lambda light chain proteins, why are kappa light chains increased?
two theories: On one theory, the kappa light chains are elevated because the kidneys are clearing them more slowly because of kidney damage. On a second theory, they're elevated because of increased production of polyclonal antibodies (for example, in the spleen).
evidence against decreased clearance: Wang 2014 tested the "decreased kidney clearance" theory by using a different reference range for the serum free light chain ratio, which was recently introduced for multiple myeloma patients with renal insufficiency. The percentage of POEMS patients with an abnormal serum free light chain ratio increased, but only from 13% to 18%, which leaves many POEMS patients who had an elevated lambda serum free light chain, but normal serum free light chain ratio.
evidence for increased production: Wang 2014 reports that in patients who had an IgA lambda clone, the uninvolved immunoglobulins (IgG + IgM) were correlated with the serum free kappa light chains. Since the uninvolved immunoglobulins aren't affected by the monoclonal problem, this suggests that the elevated kappa chains are caused by increased production of polyclonal immunoglobulins. IgG was the main component. In patients who had an IgG lambda clone, the uninvolved immunoglobulins (IgA and IgM) were not correlated with the elevated kappa chains, which isn't surprising since most of the polyclonal immunoglobulin is IgG. This also explain the fact that splenamegaly was more frequent in patients with a normal serum free light chain ratio: the splenamegaly is caused by increases in polyclonal plasma cells in the spleen (as suggested by Stankowski-Drengler 2010 p.433).
how new is this? Stankowski-Drengler 2010 concluded: 'the cause for normal [free light chain ratio] in patients with elevated [lambda free light chain] is multifactorial, i.e., related to both subclinical renal impairment and a background of potentially extramedullary [sc. lymph node, spleen, liver] polyclonal plasma cell activation' (p.433). Wang 2014 presents more evidence for that conclusion. They also infer, from the extended renal reference range results, 'that renal impairment might not be the main reason for a normal [serum free light chain ratio]'.
pleural effusions
what we knew before this article- Pleural effusion (fluid in the space around the lungs) is common in POEMS; for example, Dispenzieri 2014, table III (p.217) reports that in six large retrospective series, 3% to 43% of POEMS patients had pleural effusions.
- Pleural effusion meets a minor criterion for a POEMS diagnosis ("extravascular volume overload").
- In Cui 2014, 41 of 96 POEMS patients (42.7%) had pleural effusions. As is typical in POEMS, fluid accumulations were common: 36 (37.5%) had ascites, 25 (26.0%) had pericardial effusion, and 18 (18.8%) had all three. 57 (59.4%) had peripheral edema.
- They found six risk factors significantly correlated with pleural effusions (with VEGF, C3, and TNF-α independent risk factors):
- increased serum VEGF
- increased complement component 3 (C3)
- increased lambda light chains
- increased TNF-α
- increased IL-6
- low albumin
- cardiac disease
- The pleural fluid was an exudate in all 12 studied patients, which suggests that the fluid resulted from inflammatory changes (for example, increased vascular permeability, perhaps from high VEGF levels).
- 38 patients (39.6%) had pulmonary artery hypertension.
- They used Dispenzieri's 2003 diagnostic criteria, and not the most recent diagnostic criteria.
- They also used Light's criteria to determine that the pleural fluids were exudates, which according to this emedicine article misclassify about 20-25% of transudates as exudates.
neuropathy
what we knew before this articleNeuropathy is required for a POEMS diagnosis by the current diagnostic criteria; many studies have shown that POEMS neuropathy involves both demyelination and axonal degeneration. (The myelin sheath around nerves insulates nerves and speeds up their signal; the axon actually carries the electrochemical signal.) The demyelination seems to be more proximal (closer to the center of the body), while the axonal degeneration is more distal (further from the center of the body). Lower limbs are more affected than upper limbs.
this study adds an argument that the first effects of POEMS are due to demyelination, with axonal damage coming later- Liu 2014 studied 37 consecutive patients with newly diagnosed POEMS syndrome; none had received prior treatment; the mean time from the origin of the neuropathy to diagnosis was 10 months (and presumably the EMG/NCS were done approximately when the diagnosis was made)
- They confirmed that lower limbs were more affected than upper limbs.
- They found demyelination in some nerves with no apparent axonal damage; in other nerves, they found demyelination likely coexisting with axonal damage.
- They had follow-up EMG/NCS for three patients (apparently the three who received no treatment (p.19)), which confirmed that the decreased motor conduction velocity was the earliest manifestation of the neuropathy (p.21).
- They conclude that the nerve damage in POEMS initially is due to demyelination, and axonal damage occurs later (likely secondary to demyelination).
- The results they give from one patient tested three times (table 3, page 22) are striking enough that I'll copy them here:
| nerve | duration (months) | motor conduction velocity (m/s) | amplitude (mV) | distal motor latency (ms) | Medical Research Council (muscle strength) score | spontaneous activity | |
| right median [arm] | 2 | 40.0 | 15.7 | 4.4 | 5 | 0 | |
| 8 | 36.0 | 13.8 | 4.5 | 5 | 0 | ||
| 13 | 17.7 | 0.6 | 5.1 | 3 | 2 | ||
| right fibular [leg] | 2 | 32.0 | 9.6 | 6.2 | 5 | 0 | |
| 8 | 22.0 | 6.7 | 6.1 | 3 | 2 | ||
| 13 | -* | 0 | -* | 0 | 3 | ||
| *Could not be obtained because no CMAP response was evoked. | |||||||
caveat
- They used Dispenzieri's 2003 diagnostic criteria, not the most recent criteria.
monitoring for relapses
- Wang 2014a followed serum VEGF and total P1NP in six relapsed patients (five originally treated by melphalan-dexamethasone, one by auto). All received lenalidomide-dexamethasone after relapse. Both VEGF and P1NP were elevated at relapse, and in the four patients who went into a second remission, both dropped.
imaging bone lesions
what we knew before this article- Several articles have claimed that CT is more useful than 18-FDG PET-CT, but (as far as I know) no published articles had compared them in detail.
- Glazebrook 2014 reviewed 24 patients, newly diagnosed at Mayo from 1998-2008, who had both skeletal surveys and either PET/CT or CT.
- Every patient had at least one skeletal lesion visible on CT--the number ranged from 2 to more than 60. The most common locations were the pelvis, then the spine, lower extremities, sternum, and clavicle.
- Most patients had many small lesions; 18 (75%) had at least 5 lesions < 1 cm.
- Small lesions were sclerotic (that is more dense, showing up as bright on x-rays); larger lesions had a lytic (dark, less dense) core with a sclerotic rim.
- PET showed increased activity in only 15 of the 24 patients, mostly in the lytic center, and less often in the sclerotic margin. No sclerotic lesions less than 6 mm in size were FDG avid; all greater than 2 cm in size were FDG avid.
- Skeletal surveys of eight of the patients were initially read as negative (but three had lesions that were initially misread as small presumed bone islands). (I'm confused about the numbers here. The article says 36% three times, eight twice, and table one lists nine. The second page claims that 23 patients had skeletal surveys within two weeks of having the PET/CT, but elsewhere the article at least seems to suggest all 24 did. But whichever numbers are correct, skeletal surveys often missed lesions that were visible on CT.)
- One way to help distinguish POEMS lesions from bone islands in this study was that on CT the sclerotic lesions < 1 cm in size were well circumscribed, and did not have a feathered or brush border.
- Two patterns of post-treatment change occurred: (a) increased sclerosis, and (b) decrease in size (with complete resolution of the lesions in two patients)
(The article also briefly summarizes two articles about bone scans (scintigraphy) and one about MRI. It adds a report of an MRI study in one patient [figure 1].)
treatment
lenalidomide (Revlimid)
- Ueda 2014 found that very low dose lenalidomide and dexamethasone was beneficial for one patient; they reduced the dose to 5 mg (for the standard 21 days of a 28-day cycle, with 10 mg/wk dexamethasone), because the patient's renal function deteriorated at 10 mg. The patient's massive ascites disappeared by the end of the 7th course of very-low-dose treatment, and his VEGF normalized by the 12th month. So, patients who can't tolerate lenalidomide at normal doses might consider trying this very low dose.
- Zagouri 2014 pooled 47 published cases and 4 new cases of POEMS treated with lenalidomide (most with a combination of lenalidomide and dexamethasone). As they note (p.2019), this pooling is questionable, since different combinations and doses of drugs were used. Still, the results are striking: 93.9% of patients had not progressed at 12 months (p.2021), patients improved significantly (for example, neuropathy improved in 46/50 patients (92.0%) and stabilized in the other 4 (8%)) (pp.2020-2021), and lenalidomide was well tolerated (p.2021). Further, in all cases in which an auto was planned after treatment with lenalidomide, enough cells were collected, and no particular problems were noted (p.2021). Unfortunately, we still have a lot to learn about using lenalidomide in POEMS, as they conclude: 'Hence, the exact role of lenalidomide in the treatment of POEMS syndrome remains to be established; it may be effective as an initiating treatment prior to ASCT, in patients who require rapid disease control, as treatment for relapse after ASCT, as possible consolidation treatment after ASCT or even as an alternative option in cases refractory to conventional treatment.' (p.2021)
autologous stem cell transplant
2014 added several series of POEMS patients treated with autos, but the follow-up periods are still short, and as far as I can see these articles simply confirm what we already believed:
Nakaseko 2014- 23 patients, median follow-up 45 months, with a 96% three-year overall survival rate, and 81% three-year progression-free survival rate
- 5 (21.5%) experienced engraftment syndrome, but all responded well to corticosteroids
- 65% had a complete hematological response; 22 (95.6%) had improved clinical symptoms (with the overall neuropathy limitations score improving gradually and most becoming able to walk without support) and reduced VEGF
- five patients experienced relapse (the article says nothing more about them)
- 7 patients, median follow-up 30 months (range 10-83 months), with estimated 5-year progression-free survival of 86% and overall survival 100%
- 1 patient had engraftment syndrome; two experienced fungal pneumonia, one experienced pulmonary embolism; all fully recovered
- hematological response: 3 (43%) complete, 3 (43%) very good, 1 (14%) partial
- all experienced complete or significant resolution of clinical symptoms
- one patient relapsed 3 years after auto; one patient died 6 years after auto due to gastrointestinal bleeding unrelated to POEMS
bibliography
- Cui 2014
- Cui RT, Yu SY, Huang XS, Zhang JT, Tian CL, Dou LP, Pu CQ. 'Incidence and risk factors of pleural effusions in patients with POEMS syndrome.' Hematological Oncology (published online 2014 Feb 11).
- Dispenzieri 2012
- Dispenzieri, A. 'POEMS syndrome: update on diagnosis, risk-stratification, and management.' American Journal of Hematology 2012 Aug;87(8):804-14.
- Dispenzieri 2014
- Dispenzieri A. 'POEMS syndrome: 2014 update on diagnosis, risk-stratification, and management.' American Journal of Hematology 2014 Feb;89(2):214-23.
- D'Souza 2011
- D'Souza A, Hayman SR, Buadi F, Mauermann M, Lacy MQ, Gertz MA, Kyle RA, Kumar S, Greipp PR, Lust JA, Russell SJ, Zeldenrust S, Dingli D, Witzig TE, Rajkumar SV, Dispenzieri A. 'The utility of plasma vascular endothelial growth factor levels in the diagnosis and follow-up of patients with POEMS syndrome.' Blood 2011 Oct 27;118(17):4663-5.
- Glazebrook 2014
- Glazebrook K, Bonilla F L G, Johnson A, Leng S, Dispenzieri A. 'Computed tomography assessment of bone lesions in patients with POEMS syndrome'. European radiology published online 25 September 2014.
- Li 2013
- Li J, Zhou DB. 'New advances in the diagnosis and treatment of POEMS syndrome.' British Journal of Haematology 2013 May;161(3):303-15.
- Liu 2014
- Liu M, Zou Z, Guan Y, Li J, Zhou D, Cui L. 'Motor Nerve Conduction Study and Muscle Strength in Newly-Diagnosed Poems Syndrome.' Muscle & Nerve 51 (January 2015) 19-23 (published online 18 April 2014).
- Nakaseko 2014
- Nakaseko C. 'Autologous stem cell transplantation for POEMS syndrome.' Clinical Lymphoma Myeloma and Leukemia 2014 Feb;14(1):21-3. Epub 2013 Dec 22.
- Patel 2014
- Patel K, Nusrat M, Shah N, Bashir Q, Parmar S, Shah J, Thomas S, Weber D, Orlowski RZ, Champlin R, Qazilbash MH. Bone Marrow Transplantation 2014 Mar;49(3):465-6. 'Durable responses with autologous hematopoietic SCT in patients with POEMS syndrome.'
- Stankowski-Drengler 2010
- Stankowski-Drengler T, Gertz MA, Katzmann JA, Lacy MQ, Kumar S, Leung N, Hayman SR, Buadi F, Kyle RA, Rajkumar SV, Dispenzieri A. 'Serum immunoglobulin free light chain measurements and heavy chain isotype usage provide insight into disease biology in patients with POEMS syndrome.' American journal of hematology 85 (June 2010) 431-4.
- Ueda 2014
- Ueda S, Yonemoto S, Oka K, Fujii N, Nakata K, Matsunaga H, Kataoka S, Iwama Y, Narahara H, Yasunaga Y, Inui Y, Kawata S. 'Lenalidomide and Dexamethasone for a Patient of POEMS Syndrome Presenting with Massive Ascites.' Case Reports in Hematology 2014;2014:818946.
- Wang 2014
- Wang C, Su W, Zhang W, Di Q, Duan MH, Ji W, Cao XX, Zhou DB, Li J. 'Serum immunoglobulin free light chain and heavy/light chain measurements in POEMS syndrome'. Annals of Hematology 2014 Jan 31. [Epub ahead of print]
- Wang 2014a
- Wang C, Zhou YL, Cai H, Cheng XQ, Zhang W, Kang WY, Qin XZ, Duan MH, Han HJ, Cao XX, Zhou D, Li J. Haematologica 2014 Jun;99(6):e78-80. 'Markedly elevated serum total N-terminal propeptide of type I collagen is a novel marker for the diagnosis and follow-up of patients with POEMS syndrome.'
- Zagouri 2014
- Zagouri F, Kastritis E, Gavriatopoulou M, Sergentanis TN, Psaltopoulou T, Terpos E, Dimopoulos MA. 'Lenalidomide in patients with POEMS syndrome: a systematic review and pooled analysis.' Leukemia and Lymphoma 55 #9 (Sep 2014) 2018-2023.