Erythropoietin Treatment in Multiple Myeloma – Friend or Foe?

Abstract 5013

Erythropoietin (Epo), mainly produced by the adult kidney, is the major hormone that promotes erythropoiesis. As such, clinical introduction of recombinant human Epo (rHuEpo) and its derivatives (Epoetins), has been a breakthrough in treating patients with anemia, mainly those with chronic kidney failure and cancer patients on chemotherapy. In contrast to 'red flags' suggesting possible detrimental effects of Epo in certain cases of cancer, the hormone was found by numerous studies to have beneficial effects such as neuroprotective and cardio-protective effects. Immune-mediated anti-cancer effects were also documented, as exemplified in multiple myeloma (MM) patients and mouse models. These effects, at least in part, are mediated by Epo receptors (EpoRs) present on cells other than the erythroid lineage. In this respect, we have recently identified functional EpoRs in murine bone marrow-derived macrophages.

MM is characterized by clonal proliferation of malignant plasma cells that produce a pathological paraprotein, accompanied by a decrease in the levels of the normal immunoglobulins. Typically this disease is associated with lytic bone lesions. In 5T33 MM, an experimental murine model of MM (producing an IgG2bk paraprotein), mice that were treated with rHuEpo, displayed a 50% decrease in the levels of the pathological K light chain. Notably, the decline in the levels of normal IgA, typically observed in the MM mice, was attenuated in the Epo-treated MM mice. Administration of rHuEpo led to increased levels of liver (three fold increase) and splenic (ten fold increase) macrophages as determined by the number of F4/80/CD11b expressing cells. These findings were associated with an increase in the transcript levels of the Th1 cytokine IFN-g in the bone marrow of Epo-treated 5T33 MM mice as compared to diluent-treated 5T33 MM mice. As MM is typically associated with a Th2 response, Epo may have a beneficial effect in MM, by shifting the balance towards a Th1 response.

Myeloma-associated bone disease is considered a major cause of morbidity in MM patients. Using high-resolution computed tomography analysis of recovered femurs we confirmed that the 5T33 MM mice indeed exhibit bone disease. Femur trabecular bone density (bone volume/total volume) of 5T33 MM mice was 43% lower (p=0. 04) than that of their healthy control counterparts (3. 1%±0. 003 versus 4. 4%±0. 008, respectively). This decrease in bone density reflects a 38% increase (p=0. 001) in the total femur volume (4. 38mm³±0. 13 and 2. 72mm³±0. 95 in the 5T33 MM mice, compared to that of healthy mice) and no significant change in trabecular bone volume. Unexpectedly, Epo treatment of the MM mice induced a 34% reduction (p=0. 004) in trabecular bone density compared to the diluent-treated MM mice (2%±0. 007 and 3. 1%±0. 003, respectively) and 41% (p=1E-6) reduction in trabecular number (1. 54mm⁻¹±0. 266 and 2. 62mm⁻¹±0. 23, respectively). This was accompanied by a 19% increase (p=0. 006) in trabecular bone thickness in the Epo-treated MM mice (0. 043mm±0. 005 and 0. 036mm±0. 003, respectively), suggesting a mechanical compensatory mechanism in response to the extensive bone loss.

Taken together, our data demonstrate that Epo's impact extends well beyond erythropoiesis. The administration of rHuEpo may be considered as an adjunct treatment to specific anti-MM therapy in cases which require elevation of the erythrocyte counts and an enhancement of the immune system. Yet, a bone protection regimen (bisphosphonates?) should be considered.

This study is supported by the Multiple Myeloma Research Foundation, to DN.