A. Nozza

A. Scarale

C. Giannotta

E. Nobile-Orazio

F. Gallia

F. Terenghi

M. Bianco

M. Fayoumi

AIR Universita degli studi di Milano

Clinical, electrophysiological and VEGF two-year response after Lenalidomide or 
Stem Cell Transplantation in patients with POEMS 
Mariangela Bianco¹, Fabrizia Terenghi¹, Francesca Gallia¹, Andrea Nozza², Antonella Scarale¹, Mohammed 
Ziad Fayoumi¹, Claudia Giannotta¹, Eduardo Nobile-Orazio¹ 
1. Department of Medical Biotechnology and Translational Medicine, Milan University, Neuromuscular and 
Neuroimmunology Service, Humanitas Clinical and Research Center, Rozzano (Milan), Italy 
2. Department of Medical Oncology and Haematology, Humanitas Clinical and Research Centre, Rozzano 
(Milan), Italy 
Correspondence to: 
 Prof. Eduardo Nobile-Orazio, Department of Medical Biotechnology and Translational Medicine, Milan 
University, Neuromuscular and Neuroimmunology Service, Humanitas Clinical and Research Center, 
Rozzano (Milan) Via Alessandro Manzoni 56, Italy, e-mail eduardo.nobile@unimi.it, telephone +39 02 8224 
2209. 
 
Word Counts: 996  
Reference number: 5 
 
Keywords: POEMS, VEGF, Haematopoietic stem cell transplantation, lenalidomide 
 
 
 
 
 
 
 
 
 
 
 
INTRODUCTION 
POEMS syndrome is a rare multisystem disease characterized by polyneuropathy (P), organomegaly (O), 
endocrinopathy (E), monoclonal gammopathy (M) and skin changes (S)[1]. A usually severe demyelinating 
and axonal neuropathy is often the most prominent and disabling clinical manifestation [2]. The pathogenesis 
of POEMS syndrome is unclear even if overproduction of vascular endothelial growth factor (VEGF) seems 
to play a major role.[1,2] Autologous haematopoietic stem cell transplantation (HSCT) is now considered the 
most effective therapy in patients with disseminated disease.[1] This therapy is however not feasible in all 
patients because of their advanced age or the presence of severe concomitant conditions. A number of 
immune or cytostatic agents have been also used with variable efficacy in POEMS,[1] including 
lenalidomide whose efficacy we recently reported in 13 of the 18 treated patients.[3] Little is known however 
on the degree of response to lenalidomide in comparison to HSCT.  
 
SUBJECTS 
We retrospectively reviewed the clinical, biological and electrophysiological data from 15 patients with 
POEMS syndrome diagnosed according the criteria proposed by Dispenzieri[1] who neurologically 
improved after therapy with lenalidomide or HSCT. All the patients had been treated and followed at our 
Institution for at least two-years. The study was approved by the IRB of our Institute and all the patients 
signed an informed consent for the review of their data. 
Six patients (4 males, 2 females; mean age at disease onset 48 years, range 41-53; mean disease duration 23 
months, range 5-76) received high-dose melphalan chemotherapy followed by HSCT. Nine patients (7 
males, 2 females; mean age at disease onset 54 years, range 44-65; mean disease duration 48 months, range 
9-226) were treated with lenalidomide (25 mg/day for 21 days every month for 10-58 cycles) and oral 
dexamethasone (40 mg weekly)[3]. These patients did not undergo HSCT because of advanced age (2), 
severe concomitant conditions (3), patient preference (2), or relapse after a previous HSCT (2). Five of them 
had not previously improved after therapy with intravenous immunoglobulins (IVIg) alone (1) or with 
corticosteroids (1) or cyclophosphamide (1), corticosteroids (1) or cyclophosphamide (1). Three patients 
treated with HSCT did not respond to previous therapy with IVIg (2) or local radiotherapy (1). In all the 
patients the clinical, electrophysiological parameters and VEGF levels were assessed,[3]  before therapy (T0) 
and one (T1) and two years (T2) after starting the therapy. Clinical response was measured with the modified 
Medical Research Council (MRC) sumscore for muscle strength, range 0 (no contraction) to 80 (normal in 
16 muscles), and the Overall Neuropathy Limitation Scale (ONLS), range 0 (normal) to 12 (unable to do any 
purposeful movement with arms and legs).  Motor conduction studies were performed on the ulnar, tibial and 
peroneal nerves, and included the measurement of distal and proximal compound motor action potential 
(CMAP) amplitudes, distal motor latency (DML) and motor nerve conduction velocity (MCV). Sensory 
conduction velocities (SCV) and sensory action potentials (SNAP) were measured in the ulnar and sural 
nerves. VEGF levels were measured by enzyme-linked immuno sorbent assay (ELISA)(normal: < 1000 
pmol/L)[3]. In each group, the difference in the clinical, electrophysiological and biological parameters 
between baseline (T0), and one (T1) and two years (T2) after therapy was assessed by analysis of variance 
(ANOVA). A probability (p) value of < 0.05 was considered statistically significant.  
 
RESULTS 
We found a significant improvement in the MRC sumscore and in the ONLS score after one and two years 
both in patients treated HSCT (p=0.001) and in patients treated with lenalidomide (p=0.002)(Table). The 
number of patients was too small for a statistical comparison of the improvement between the two groups, 
but the mean improvement was similar in the two groups.  
The frequency of nerves with no potential was higher in lower than in upper limbs with no CMAP response 
in 67% peroneal nerves, 73% tibial nerves and 73% sural nerves before and after treatment. Similarly 
infrequent was the response in the sensory ulnar nerve. We focused our study on the ulnar motor nerve. The 
mean DML of this nerve was reduced in patients treated with HSCT or lenalidomide, but the difference was 
significant only for HSCT (p=0.009; lenalidomide p=0.08). MCV significantly improved in patients treated 
with HSCT (p=0.03) and lenalidomide (p=0.0004) as did distal CMAP amplitude (HSCT p=0.009; 
lenalidomide p=0.003). We did not compare the improvement between two groups, but the mean 
improvement was similar in the two groups (Table).  
Serum VEGF levels were reduced after treatment in patients treated with HSCT or lenalidomide, but the 
difference was significant for lenalidomide (T0 vs T1:  p=0.027; T0 vs T2: p=0.046) but not for HSCT (T0 
vs T1: p = 0.156; T0 vs T2: p=0.112);. 
 CONCLUSIONS 
POEMS syndrome is a chronic progressive and often disabling disorder with estimated median survivals of 
nearly 14 years. In patients with disseminated disease, HSCT is considered the preferred treatment. Of the 59 
patients receiving HSCT at the Mayo Clinic in Rochester, progression-free survival (PFS) after a median 
follow-up of 45 months was 98% and 75% after one and 5 years respectively [4]. Lenalidomide has been 
recently reported to be effective in patients with POEMS and was not associated with neurotoxicity.[3,5] A 
recent analysis of 51 patients with POEMS syndrome showed hematologic response in 95% of the patients, a 
neurological response in 92% with a PFS at one year of 94% [5]. In our study HSCT and lenalidomide 
resulted in a significant improvement over two years in the MRC sumscore, ONLS score, and in the ulnar 
CMAP and MCV while serum VEGF levels were significantly reduced only in the lenalidomide group. Even 
if the number of treated patients was too small to compare statistically the difference in the improvement 
between the two groups, we observed a comparable degree of response in the two groups by the end of the 
first and second year.  Since HSCT may not be suitable for all patients or may be refused by others for its 
potential risks, lenalidomide may represent a valuable alternative for at least two years in these patients or in 
those relapsing after HSCT. 
  
Acknowledgments 
We wish to thank Dr. Emanuela Morenghi for statistical analysis.  We also thank Celgene, Italy, for 
providing at no cost lenalidomide for patients originally enrolled in the open label trial with lenalidomide 
and dexamethasone. The company had no role in this study. The study was supported by a contribution from 
Humanitas Clinical and Research Center. 
 
Authors’ contributions 
Study design: MB, ENO 
Experiments and procedures: FT, FG, AN, AS, MZF, CG 
Data analysis and interpretation: MB, ENO 
Manuscript drafting: MB, ENO 
Manuscript editing: All 
Approval of final draft: All 
 
Conflicts of interest 
ENO: personal fees for lecturing or Advisory/Scientific/Safety Board Membership not related to this study 
from Baxter, Italy;  CSL Behring, Switzerland;  Kedrion Biopharma, Italy; LFB, France; Novartis, 
Switzerland;   UCB, UK; Astellas Biopharma, the Netherlands. 
The other Authors have no conflicts of interests. 
 
  
 REFERENCES 
1. Dispenzieri A. POEMS syndrome: 2017 update on diagnosis, risk stratification and management. Am 
J Hematol 2017;92(8): 814-29. 
2. Mauermann ML, Sorenson EJ, Dispenzieri A, et al., Uniform demyelination and more severe axonal 
loss distinguish POEMS syndrome from CIDP. J Neurol Neurosurg Psychiatry 2012;83(5):480-6. 
3. Nozza A, Terenghi F, Gallia F, et al. Lenalidomide and dexamethasone in patients with POEMS 
syndrome: results of a prospective, open-label trial. Br  J Haematol 2017;179(5):748-755.  
4. O’Souza A, Lacy M, Gertz M, et al. Long-term outcomes after autologous stem cell transplantation 
for patients with POEMS syndrome. A single center experience. Blood 2012;120:56-62. 
5. Zagouri F, Kastritis E, Gavriatopoulou M, et al. Lenalidomide in patients with POEMS syndrome: a 
systematic review and pooled analysis. Leuk Lymphoma 2014;55:2018-23. 
  
Table 
Clinical and electrophysiological findings in patients with POEMS syndrome treated with HSCT 
and lenalidomide 
 
MRC: Medical Research Council; ONLS: Overall Neuropathy Limitation Scale; DML: Distal Motor 
Latency; MCV: motor nerve conduction velocity; CMAP: compound muscle action potential; SD: standard 
deviation 
 
  
HSCT (n=6) 
 
 
Lenalidomide (n=9) 
 
MRC (mean + SD; median) 
Time 0 
Time 1 
Time 2 
p 
 
65+13; 74 
71+11; 70 
71+7;  75 
0.001 
 
64+19; 70 
67+13; 77 
71+10; 73 
0.001 
ONLS (mean + SD; median) 
Time 0 
Time 1 
Time 2 
p 
 
5.8+3.2; 5 
3.5+2.5; 3 
  3.0+2.2; 2.5 
0.0001 
 
5.4+2.3; 6 
  3.7+1.5; 3.5 
    4+1.8; 3.5 
0.002 
Ulnar DML (msec) (mean + SD; median)  
Time 0 
Time 1 
Time 2 
p 
 
3.2+0.6; 3.4 
3.3+0.4; 3.3 
  3+0.5; 2.8 
0.009 
 
4.2+1.4; 3.8 
  3.3+5; 3.1 
                 3.2+0.4; 3.1 
0.08  
Ulnar MCV (m/sec) (mean,  median, range) 
Time 0 
Time 1 
Time 2 
p 
 
41.3+9.4; 38 
39.7+6.7; 38 
47.1+11; 47 
0.03 
 
34.7+11.3; 33 
45.2+9.9; 47 
48.6+8.7; 46 
0.0004 
Ulnar CMAP (mV) (mean, median, range) 
Time 0 
Time 1 
Time 2 
p 
 
8.6+2.1; 8.5  
8.7+2.6; 9.3  
9.7+1.4; 9.4 
0.009 
 
5.6+2.4; 6.1 
6.3+3.3; 6.7 
5.8+2.2; 6.3 
0.003 


Clinical, electrophysiological and VEGF 2-year response after lenalidomide or stem cell transplantation in patients with POEMS syndrome

https://air.unimi.it/retrieve/handle/2434/593774/1182336/letter%20Bianco%20jnnp%20rev.pdf

Clinical, electrophysiological and VEGF 2-year response after lenalidomide or stem cell transplantation in patients with POEMS syndrome

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