Erythropoietin Treatment in Advanced Multiple Myeloma Is Associated with Improved Immunological Functions: Could It Be Beneficial in Early Disease?.
Authors: Prutchi-Sagiv Sara , Golishevski Nataliya , Oster Howard S. , Katz Odelia , Elizabeth Naparstek , Cohen Amos , Hoffman Michael , Neumann Drorit , Mittelman Moshe 
Published: October 2019

Abstract
Erythropoietin (Epo), the main growth regulator of erythropoiesis, is being used to treat anemias associated with renal disease and malignancies. We have previously observed prolonged survival of patients with advanced multiple myeloma (MM) who were treated with recombinant human Epo (rHuEpo) (Mittelman et al, Eur J Haematol2004:72:155). Further studies on murine MM models confirmed this observation and suggested that Epo has an anti-MM immunomodulatory effect (Mittelman et al. Proc Natl Acad Sci USA2001:98:5181; Katz et al. Acta Haematol2005:114:177). We have reported (ASH 2004) preliminary results showing that the rHuEpo-treated MM patients acquired improved immunological functions. We have since then extended the numbers of patients and the range of immunological functions tested. Here, we show that rHuEpo, prescribed for anemia in patients with advanced MM (Durie and Salmon Stage 2–3), is associated with effects on a variety of immunological parameters and functions, as presented in the table. Compared with non rHuEpo-treated MM patients, who demonstrated immunological abnormalities, rHuEpo-treated MM patients resumed normalization of the CD4:CD8 cell ratio, enhanced T-cell (both CD8 and CD4) PHA-mediated activation, improved mononuclear proliferation potential, higher expression of the co-stimulatory molecule CD28, lower values of the inhibitory CTLA-4 molecule and decreased levels of serum IL-6. The immunological parameters in the rHuEpo-treated MM patients were close to the normal healthy controls. Results are presented in the table below (mean +/− SE). We also found similar immunological abnormalities in patients at an early stage (Durie and Salmon stage 1, smoldering) MM (n=8).
Our findings a) confirm and extend reports by others regarding immunological abnormalities in patients with advanced MM; b) show that patients with advanced MM treated with rHuEpo for their anemia benefit from improved immunological functions; c) show that patients with early-stage MM already manifest similar immunological abnormalities. Our data thus indicate that patients with early-stage MM might benefit from rHuEpo with improved immune functions, even prior to the development of anemia in later stages of the disease. Taken together, our study suggests rHuEpo as a potential immunomodulatory agent in the treatment of MM.
Parameter Normal Healthy Controls MM Patients rHuEpo-treated Advanced MM Patients Early MM Advanced MM a. p<0.05 advanced MM compared to healthy controls. b. p<0.05 early MM compared to health controls. c. p<0.05 rHuEpo treated advanced MM compared to non-treated advanced MM patients Number of Patients N=14 N=8 N=21 N=13 CD4:CD8 2.4±0.3 1.2±0.2b 1.2±0.1a 1.9±0.3c PHA act- CD8+CD69+ (%) 60±4.4 45±4.4b 46.3±3a 63.3±3.8c PHA act-CD4+CD69+ (%) 57.1±3.8 42±4.6b 43.3±3a 59.9±3.6c Proliferation (%) 232.5±10.3 161±7.1b 146.5±15.1a 218.1±22.5c CD8+CD28+ (%) 73.2±5.2 53.7±8.2 38.8±2a 55.6±2.9c CD8+CTLA-4+ (%) 2.4±0.6 12.5±3.6 10.1±1.5a 4.6±0.9c sIL-6 (pg/ml) 2.6±0.4 5.4±1 10±2.1a 5.7±0.9c