2016 update on POEMS syndrome

I apologize for taking so long to finish this. Please contact me with questions, corrections, or suggested additions!

Index

cause: VEGF; cytokines other than VEGF; kidney damage
symptoms: calciphylaxis
treatment: thalidomide; autologous stem cell transplant; lenalidomide (Revlimid); ixazomib
response: kidney problems
prognosis: prognosis; survival
bibliography: works published in 2016; other

cause--VEGF

Monoclonal plasma cells play a crucial role in POEMS (as we know since therapies that attack them help POEMS patients dramatically). But the damage in POEMS is not caused directly by monoclonal plasma cells or the monoclonal protein they produce, but rather by abnormal cytokines produced as a result of the monoclonal plasma cell proliferation.(Cytokines are chemicals cells use to communicate with each other--like hormones, but produced all around the body, not in one central location.) Of the studied cytokines, VEGF is the best correlated with POEMS activity (see Dispenzieri 2015 p.953 for the evidence). But very little evidence has been available about its production.

Wang 2016c found that VEGF is produced in plasma cells in bone marrow. Strikely, it is produced as intensely in polyclonal plasma cells in bone marrow as it is in monoclonal cells. They suggest that the monoclonal plasma cells may encourage growth of polyclonal plasma cells (perhaps by producing IL-6). This might help explain why small clones of plasma cells can produce so many problems in POEMS (see p.83).

(The article they cite to show that IL-6 causes reactive plasmacytosis, Jego 1999, shows that IL-6 is required for plasmoblasts to differentiate into plasma cells, and doesn't obviously show a "stimulatory effect of IL-6 on reactive plasmacytosis". But there is evidence IL-6 does stimulate growth of plasma cells; for a summary, see, for example, CIBA Foundation Symposium, Polyfunctional cytokines: IL-6 and LIF (John Wiley & Sons, 2008), pp.189 sqq. (available on Google Books).)

cause--cytokines other than VEGF

Extravascular fluid overload is common in POEMS (29% to 87% in different studies [Dispenzieri 2015]), perhaps due to increased VEGF (which increases vascular permeability). But VEGF isn't the whole story. Bevacizumab, which is a monoclonal antibody to VEGF, has had very mixed results, with some people showing possible improvement, but others dying quickly. Yamada 2013 found that basic fibroblast growth factor (bFGF) and hepatocyte growth factor (HGF) are also elevated in POEMS. Like VEGF, HGF increases vascular permeability; bFGF, on the other hand, increases the blood-nerve barrier. Since bevacizumab reduced VEGF but not HGF, Yamada 2013 suggested that HGF might be responsible for deaths after reduction of VEGF by bevacizumab, and might be responsible for problems POEMS patients experience without increasing levels of VEGF. Alternatively, perhaps reducing VEGF rapidly causes new blood vessels to collapse (Straume 2006, also cited in Sekiguchi 2013).

Muto 2016 reports cytokine levels in two patients whose extravascular volume overload increased dramatically after they were given cyclophosphamide and G-CSF to mobilize stem cells for an autologous stem cell transplant, from before and after the mobilization. In both, serum VEGF was lower after mobilization, suggesting it did not cause the volume overload. In one patient, serum VEGF was reduced from 8160 pg/mL 29 days before administration, and 1210 pg/mL when the stem cells were collected. In the other, serum VEGF was 1360 pg/mL 163 days before administration, 883 pg/mL 122 days before (after she received thalidomide), 2540 pg/mL 70 days before, and 1850 pg/mL 30 days before (after three additional courses of thalidomide). Her serum VEGF was reduced to 117 pg/mL 3 days after administration.

Pro-inflammatory cytokines increased in both. In patient 1, IL-6 increased from 16.6 to 45 pg/mL; in patient 2, IL-6 increased from 8.6 pg/mL to 63.0 pg/mL on day 3. In one of the patients, MIP-1α and the Il-1β to IL-1ra ratio also increased. The authors note that Li 2013c suggests G-CSF might increase pro-inflammatory cytokines; perhaps the pro-inflammatory cytokines resulted in capillary leak syndrome. (I don't see that suggestion in Shimizu 2012b, which they also cite.) The authors also note that the reduction in VEGF may be relevant (as suggested by Straume 2006).

I do not know why they did not measure HGF, which increases vascular permeability, and which Yamada 2013 found was elevated in POEMS and not affected by anti-VEGF antibodies (bevacizumab (Avastin).

Other interesting cytokine results are these:

IL-12 was elevated in both patients before G-CSF and cyclophosphamide, and reduced after. [Kanai 2012 showed that IL-12 is elevated in POEMS patients and decreased after treatment; since IL-12 is neurotoxic, it might be the neurotoxin elevated VEGF allows to cross the blood-nerve barrier, damaging nerves]
bFGF was in-range in both patients; HGF was not tested [Yamada 2013 found that both bFGF and HGF are elevated in POEMS]
IL-13 was high in one, but in-range after mobilization [Keyzner 2013 found that higher pretransplant and posttransplant IL-13 was correlated with delayed neutrophil engraftment]
IL-1ra was in-range in both [Keyzner 2013 found that low posttreatment IL-1ra was correlated with engraftment syndrome]
IFN-γ, IL-4, and IP-10 were in-range in both [Keynzer 2013 found they were significantly higher in POEMS patients]
IL-10 was high in both before mobilization, but in-range in one after [Keyzner 2013 found IL-10 was significantly higher in POEMS patients]
[Muto 2016 checked whether cytokines were outside the mean +/- 3 standard deviations; Keyzner 2013 compared POEMS and non-POEMS cytokines using the Mann-Whitney rank-sum test]

cause--kidney damage

Ye 2016 provides evidence that VEGF is responsible for kidney damage in POEMS. Baseline VEGF levels were not different in patients with renal insufficiency than in patients without, but VEGF remission was significantly associated with renal response to treatment (though at p=0.050), and everyone whose VEGF was reduced at least 85.8% responded (while 70% of those who responded had VEGF reduced at least that much).

In this study, 22.4% of patients had eGFR less than 60 (using the CKD-EPI equation), compared with 2% of patients with serum creatinine greater than 1.5 mg/dL in Dispenzieri 2003. They suggest a longer time to diagnosis might have resulted in increased damage. (However, the more recent Stankowski-Drengler 2010 found that 15% of POEMS patients had serum creatinine greater than 1.5 mg/dL (and 31 (72%) had elevated cystatin C, suggesting subclinical renal damage is very common).)

symptoms--calciphylaxis

Calciphylaxis involves calcium deposits in small blood vessels along with skin ulcers and skin death. It usually occurs in patients on dialysis, but seven cases of calciphylaxis in POEMS patients who are not on dialysis have been reported. (Araki 2016 cites De Roma 2004, Hinero 2009, Lee 2011, Heck 2014, and Novoa 2014; add Yoshikawa 2011 and Bourgeault 2015.)

Araki 2016 reviewed 75 POEMS patients (all those seen at Chiba University Hospital from 1992 to 2013, except for one on dialysis) and 86 controls. They found CT evidence of small-vessel calcification in 13 (17%) patients with POEMS and in none of the controls, and skin ulcers in 3 (4%) of the POEMS patients and none of the controls. (The incidence of large-vessel calcification, presumably from age and atherosclerosis, was similar in the two groups.) While this isn't conclusive evidence of calciphylaxis (though autopsies of two patients did show calciphylaxis), it does make calciphylaxis probable (see pp.3, 4-5). More of the POEMS patients with calciphylaxis had significant neuropathy, more had ascites, the mean IL-6 level was higher, and the mean albumin level was lower, than in the POEMS patients who did not have calciphylaxis (p.5). But traditional risk factors for calciphylaxis (e.g. serum calcium and phosphate) were not different. They speculate that increased levels of cytokines, perhaps including IL-6, might cause small-vessel calcification in POEMS.

treatment--thalidomide

Misawa 2016 reports the results of the JPOST trial of thalidomide (see Katayama 2015 and Misawa 2015), which is the first randomized, placebo-controlled, double-blind, study of any treatment for POEMS. In the first phase, which tested efficacy, they found that thalidomide-dexamethasone reduced VEGF more than placebo. (However, the difference was significant at 24 weeks, and not significant from 0 to 20 weeks.) They found that thalidomide did cause sinus bradycardia (in 7 patients in the thalidomide group, and none in the placebo group), but it was relatively mild. Thalidomide did not worsen peripheral neuropathy in the first phase, but mild sensory neuropathy did occur in 5 of 22 patients in the second phase. They conclude that thalidomide is safe and effective, and should be an option in treating POEMS.

They also conclude that long-term placebo-controlled trials for POEMS will not be practicable or defensible, since nine of the twenty four patients in the first phase had to be transferred to the open-label study because either their neuropathy worsened or they had increased edema or pleural effusion. Also, two patients who were initially in the placebo group died of disease progression during the open-label part of the study.

(The placebo group received thalidomide in the second phase; they were noticably worse at the end than the thalidomide group was after the initial 24 weeks, presumably because they received thalidomide without dexamethosone (I assume because this phase was testing safety and not efficacy).)

treatment--autologous stem cell transplant

Cook 2016, which is the largest published series of POEMS patients receiving an autologous stem cell transplant (127 patients), confirms that autos are safe and effective for POEMS.

Unfortunately, since it was a multicenter retrospective study, they do not have all the data we might hope for; for example, VEGF was not measured routinely. And since they use different definitions of some key features than the well-characterized Mayo series (D'Souza 2011, supplemented by Karam 2015 and Chandrashekeran 2015), the results are sometimes not directly comparable. For example, only 23% of patients in Cook 2016 experienced peri-transplant engraftment syndrome, compared to 37% in D'Souza 2011, but Cook uses a standard definition of engraftment syndrome, while D'Souza relaxed the requirement that symptoms occur within 96 hours of neutrophil engraftment. And 48% of the evaluable patients experienced complete hematologic response, compared with 57% in D'Souza, although Cook has a less stringent definition. Both studies showed similar rates of successful engraftment (97% in Cook, 98% in D'Souza). Cook (with a median follow-up of 48 months) had progression-free survival of 84% at 3 years, while D'Souza (with a median follow-up of 45 months) had progression-free survival of 98% at 1 year and 75% at 5 years. Cook found that 'the status at transplant (C[omplete]R[esponse] vs < CR)' was not significantly correlated with progression-free survival, while Kourelis 2016 found that complete response after treatment is; Kourelis 2016 also found that pre-treatment albumin is, but Cook notes that only about a third of patients had baseline albumin levels available.

treatment--lenalidomide (Revlimid)

Zagouri 2014 found that lenalidomide reduced VEGF in all reported cases of treatment for POEMS. In Yang 2016, after twelve cycles of lenalidomide (Revlimid)-dexamethasone, mean serum VEGF decreased (but the mean was still out-of-range high). (VEGF was out-of-range high in 38 of 39 patients before treatment; I did not see the equivalent figure for post-treatment VEGF.) Sexual function also improved significantly.

(The numbers in the study are not clear to me: they started with 41 consecutive patients, excluding two because they were not sexually active, two who died during follow-up, and two who 'retreated' (presumably withdrew from the study), but they report results for 38 patients, not 35.)

treatment--ixazomib

Mayo Clinic has started a study of ixazomib citrate (Ninlaro), lenalidomide (Revlimid), and dexamethasone (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.

response--kidney problems

In Ye 2016, two-thirds of the patients with renal dysfunction and post-treatment renal function tests improved after treatment, with improvement in 50.0% of the 14 receiving melphalan, 85.7% of the 7 receiving autologous stem cell transplants, 81.8% of the 22 receiving novel agents (most lenalidomide (Revlimid), but also bortezomib (Velcade), and thalidomide), and 0.0% of the 4 receiving other treatment (including steroid monotherapy, traditional Chinese medicine, and no treatment). The median time to renal response was 4.8 months (shorter with novel agents than with other treatment).

prognosis

D'Souza 2012 found that POEMS patients were more likely to progress after an autologous stem cell transplant if they had an IgG-λ m-protein, they had FDG-avid lesions on PET scan before the auto, they did not achieve complete hematologic response after the auto (which required a negative bone marrow, and negative urine and serum immunofixation), or they were 50 years or younger when they were transplanted. Further, Misawa 2015 found that serum VEGF six months after treatment was well correlated with relapse-free survival three years after treatment; see also D'Souza 2012.

Two studies added further information about prognosis. Kourelis 2016a (which overlaps with Kourelis 2016, which I discussed in last year's update) found three independent factors correlated with superior progression-free survival: younger age, normal serum albumin at diagnosis and achieving complete hematologic response after treatment. (Baseline VEGF was not tested because it was available for only 47 of the patients.) Wang 2017 found four independent factors correlated with inferior overall survival: age > 50 years, pulmonary hypertension, pleural effusion, and estimated glomerular filtration rate < 30 ml/min/1.73 m^2. (Baseline VEGF was available for 295 patients, and was greater than 2000 pg/mL in 228 (77%), but did not predict survival (pp.101, 104). They did not measure response to treatment because their center drew patients from more than 30 institutions (see pp.100, 105).)

The differences between the studies may be due in part to differences in the patient population, differences in the endpoint (progression-free survival for Kourelis 2016, and overall survival for Wang 2017), differences in treatment (in particular Wang 2017 did not use radiation; see Li 2011 pp.824-5 and Li 2013 p.6 for explanation), and the fact that Wang 2017 study did not consider response to treatment.(See the very useful discussion on Wang 2017 p.105, which discusses the earlier-published Kourelis 2016, and not Kourelis 2016a.) Also, Kourelis 2016a didn't consider estimated glomerular filtration rate since only two patients had an eGFR less than 30 (p.587).

Another study adds that patients with monoclonal plasma cell populations in bone marrow detected by flow cytometry were less likely to have complete hematological response than others. (Flow cytometry is less sensitive than immunohistochemistry and in situ hybridization; see Dao 2011, which this article confirms.) Only 1 of 11 (9.1%) patients with monoclonal plasma cells detectable by flow cytometry achieved complete hematological response. Of other patients, 26 of 51 (51.0%) did. (Wang 2016c, page 83)

survival

The available evidence about survival was out of date; two studies from Mayo found that 99 POEMS patients seen at Mayo from 1960 to 1998 had an overall median survival of 165 months (Dispenzieri 2003), and 137 POEMS patients seen at Mayo from 1975 to 2003 had an overall median survival of 147 months (Allam 2008). But treatment has improved significantly since 2003.

Two large retrospective studies added information about survival: both suggest that the current 10-year overall survival rate is about 78%.

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%.

Bibliography

Published (or pre-published) in 2016

Araki 2016: Araki N, Misawa S, Shibuya K, Ota S, Oide T, Kawano A, Beppu M, Nakatani Y, Kuwabara S. 'POEMS syndrome and calciphylaxis: an unrecognized cause of abnormal small vessel calcification'. Orphanet J Rare Dis. 2016 Apr 12;11:35. doi: 10.1186/s13023-016-0421-3.
ClinicalTrials.gov NCT02921893: 'Ixazomib Citrate, Lenalidomide, and Dexamethasone in Treating Patients With POEMS Syndrome'. Principal investigator: Angela Dispenzieri.
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 2016 Sep 15. pii: haematol.2016.148460. [Epub ahead of print]
Kourelis 2016a: Kourelis TV, Buadi FK, Kumar SK, Gertz MA, Lacy MQ, Dingli D, Go RS, Kapoor P, Lust JA, Hayman SR, Hwa Y, Rajkumar SV, Zeldenrust SR, Russell SJ, Lin Y, Leung N, Kyle RA, Gonsalves WI, Dispenzieri A. 'Long-term outcome of patients with POEMS syndrome: An update of the Mayo Clinic experience'. American journal of hematology 2016 Jun;91(6):585-9. doi: 10.1002/ajh.24356.
Misawa 2016: Misawa S, Sato Y, Katayama K, Nagashima K, Aoyagi R, Sekiguchi Y, Sobue G, Koike H, Yabe I, Sasaki H, Watanabe O, Takashima H, Nishizawa M, Kawachi I, Kusunoki S, Mitsui Y, Kikuchi S, Nakashima I, Ikeda S, Kohara N, Kanda T, Kira J, Hanaoka H, Kuwabara S; Japanese POEMS Syndrome for Thalidomide (J-POST) Trial Study Group. 'Safety and efficacy of thalidomide in patients with POEMS syndrome: a multicentre, randomised, double-blind, placebo-controlled trial'. Lancet Neurology 2016 Oct;15(11):1129-37. doi: 10.1016/S1474-4422(16)30157-0.
Muto 2016: Muto T, Ohwada C, Sawai S, Beppu M, Tsukamoto S, Takeda Y, Mimura N, Takeuchi M, Sakaida E, Sogawa K, Misawa S, Shimizu N, Iseki T, Nomura F, Kuwabara S, Nakaseko C. 'Acutely deteriorated extravascular volume overload during peripheral blood stem cell mobilization in POEMS syndrome: A case series with cytokine analysis'. Transfusion and apheresis science 2016 Apr;54(2):276-81. doi: 10.1016/j.transci.2015.10.016. Epub 2015 Nov 4.
Wang 2016c: Wang C, Huang XF, Cai QQ, Cao XX, Cai H, Zhou D, Li J. 'Remarkable expression of vascular endothelial growth factor in bone marrow plasma cells of patients with POEMS syndrome'. Leuk Res. 2016 Sep 26;50:78-84. doi: 10.1016/j.leukres.2016.09.017.
Wang 2017: C Wang, X-F Huang, Q-Q Cai, X-X Cao, M-H Duan, H Cai, D-B Zhou and J Li. 'Prognostic study for overall survival in patients with newly diagnosed POEMS syndrome'. Leukemia 31 (2017) 100-106; advance online publication, June 24, 2016. doi:10.1038/leu.2016.168
Yang 2016: Yang H, Huang X, Cai Q, Wang C, Cao X, Zhou D, Li J. 'Improvement of sexual function in POEMS syndrome after combination therapy of Lenalidomide and dexamethasone'. Orphanet J Rare Dis. 2016 Jun 18;11(1):80. doi: 10.1186/s13023-016-0461-8.
Ye 2016: Ye W, Wang C, Cai QQ, Cai H, Duan MH, Li H, Cao XX, Zhou DB, Li J. 'Renal impairment in patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes syndrome: incidence, treatment and outcome'. Nephrology Dialysis transplantation 2016 Feb;31(2):275-83. doi: 10.1093/ndt/gfv261.

other

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.
Bourgeault 2015: Bourgeault E, Dahl A, Thibeault MM, Dupéré A, Drolet AM, Mathieu J. 'POEMS Syndrome Complicated by Extensive Calciphylaxis: A Remarkable Recovery.' Journal of cutaneous medicine and surgery 2015 Mar 11. pii: 7750.2014.14086.
Chandreshekaran 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.
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. doi: 10.1182/blood-2011-06-362392.
D'Souza 2012: D'Souza A, Lacy M, Gertz M, Kumar S, Buadi F, Hayman S, Dingli D, Zeldenrust S, Kyle R, Ansell S, Inwards D, Johnston P, Micallef I, Porrata L, Litzow M, Gastineau D, Hogan W, Dispenzieri A. 'Long-term outcomes after autologous stem cell transplantation for patients with POEMS syndrome (osteosclerotic myeloma): a single-center experience.' Blood 2012 Jul 5;120(1):56-62. doi: 10.1182/blood-2012-04-423178.
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.
De Roma 2004: De Roma I; Filotico R; Cea M; Procaccio P; Perosa F. 'Calciphylaxis in a patient with POEMS syndrome without renal failure and/or hyperparathyroidism. A case report.' Annali italiani di medicina interna: organo ufficiale della Società italiana di medicina interna 2004 Oct-Dec; 19(4): 283-7.
Dispenzieri 2003: 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.
Dispenzieri 2015: Dispenzieri A. 'POEMS syndrome: Update on diagnosis, risk-stratification, and management.' American journal of hematology 2015 Sep 1. doi: 10.1002/ajh.24171.
Heck 2014: Heck D, Mergen M, Ganner A, Pelisek J, Mader I, Weiller C, Niesen WD. 'POEMS syndrome, calciphylaxis and focal segmental glomerulosclerosis - VEGF as a possible link'. BMC Neurology 2014 Nov 5;14(1):210. PMID: 25369758
Hinero 2009: Hineno A, Kinoshita T, Kinoshita M, Arakura F, Naito KS, Shimojima Y, Matsuda M, Yoshida K, Ikeda SI. 'Calciphylaxis as a Catastrophic Complication in a Patient with POEMS Syndrome.' Case Rep Neurol 2009 Dec 2;1(1):47-53.
Jego 1999: G Jego, N Robillard, D Puthier, M Amiot, F Accard, D Pineau, J-L Harousseau, R Bataille, C Pellat-Deceunynck. 'Reactive plasmacytoses are expansions of plasmoblasts retaining the capacity to differentiate into plasma cells'. Blood 94 (1999) 701-712.
Karam 2015: Karam C, Klein CJ, Dispenzieri A, Dyck PJ, Mandrekar J, D'Souza A, Mauermann ML. 'Polyneuropathy improvement following autologous stem cell transplantation for POEMS syndrome'. Neurology 84#19 (2015) 1981-1987.
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.
Kourelis 2016: Kourelis TV, Buadi FK, Gertz MA, Lacy MQ, Kumar SK, Kapoor P, Go RS, Lust JA, Hayman SR, Rajkumar V, Zeldenrust SR, Russell SJ, Dingli D, Lin Y, Leung N, Hwa YL, Gonsalves W, Kyle RA, Dispenzieri A. 'Risk factors for and outcomes of patients with POEMS syndrome who experience progression after first-line treatment'. Leukemia 2016 May;30(5):1079-85. doi: 10.1038/leu.2015.344
Lee 2011: Lee FY, Chiu HC. 'POEMS syndrome with calciphylaxis: A case report.' Acta Derm Venereol 2011 Jan;91(1):96-7. doi: 10.2340/00015555-0969.
Li 2011: Li J, Zhou DB, Huang Z, Jiao L, Duan MH, Zhang W, Zhao YQ, Shen T. 'Clinical characteristics and long-term outcome of patients with POEMS syndrome in China.' Annals of Hematology 2011 Jul;90(7):819-26. doi: 10.1007/s00277-010-1149-0.
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. doi: 10.1111/bjh.12236.
Li 2013c: Li J, Zhang W, Duan MH, Jiao L, Zhu TN, Han B, Zhang L, Gan J, Zhou DB. 'PBSC mobilization in newly diagnosed patients with POEMS syndrome: outcomes and prognostic factors.' Bone Marrow Transplant 2013 Feb;48(2):233-7. doi: 10.1038/bmt.2012.138.
Misawa 2015: Misawa S, Sato Y, Katayama K, Hanaoka H, Sawai S, Beppu M, Nomura F, Shibuya K, Sekiguchi Y, Iwai Y, Watanabe K, Amino H, Ohwada C, Takeuchi M, Sakaida E, Nakaseko C, Kuwabara S. 'Vascular endothelial growth factor as a predictive marker for POEMS syndrome treatment response: retrospective cohort study'. BMJ Open 2015:5:e009157. doi 10.1136/bmjopen-2015-009157
Novoa 2014: Novoa RA, Honda KS, Campagnaro E, Gerstenblith MR. 'Hypertensive emergency, matlike telangiectasias, and calciphylaxis in POEMS syndrome.' JAMA Dermatol. 2014 Jun;150(6):667-9. doi: 10.1001/jamadermatol.2013.7256.
Sekiguchi 2013: Sekiguchi Y, Misawa S, Shibuya K, Nasu S, Mitsuma S, Iwai Y, Beppu M, Sawai S, Ito S, Hirano S, Nakaseko C, Kuwabara S. 'Ambiguous effects of anti-VEGF monoclonal antibody (bevacizumab) for POEMS syndrome.' J Neurol Neurosurg Psychiatry 2013 Dec;84(12):1346-8. doi: 10.1136/jnnp-2012-304874.
Shimizu 2012: Shimizu N, Nakaseko C, Sakaida E, Ohwada C, Takeuchi M, Kawaguchi T, Tsukamoto S, Sakai S, Takeda Y, Abe D, Yokote K, Iseki T, Kanai K, Misawa S, Kuwabara S. 'Factors associated with the efficiency of PBSC collection in POEMS syndrome patients undergoing autologous PBSC transplantation.' Bone Marrow Transplant 2012 Jul;47(7):1010-2. doi: 10.1038/bmt.2011.211.
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.' Am J Hematol 2010 Jun;85(6):431-4. doi: 10.1002/ajh.21707.
Straume 2006: Straume O; Bergheim J; Ernst P 'Bevacizumab therapy for POEMS syndrome.' Blood 2006 Jun 15; 107(12): 4972-3; author reply 4973-4
Yamada 2013: Yamada Y, Sawai S, Misawa S, Kanai K, Shibuya K, Mori M, Moriya J, Sogawa K, Yamamoto H, Beppu M, Taniguchi J, Nakaseko C, Nomura F, Kuwabara S. 'Multiple angiogenetic factors are upregulated in POEMS syndrome.' Annals of hematology 92 (Jan 2013) 245-248.
Yoshikawa 2011: Yoshikawa M, Uhara H, Arakura F, Murata H, Kubo H, Takata M, Yoshida K, Okuyama R. 'Calciphylaxis in POEMS syndrome: A case treated with etidronate.' Acta Derm Venereol 2011 Jan;91(1):98-9. doi: 10.2340/00015555-0968.
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.