Multiple myeloma: multiple ways to defeat erythropoiesis

Multiple myeloma (MM) accounts for 1% of all cancer deaths and often is first suspected in an otherwise asymptomatic patient with anemia. About two-thirds of patients with newly diagnosed MM are anemic, and nearly all will eventually develop anemia during the course of their disease. The cause of anemia in MM is often multifactorial, including (1) massive marrow invasion by myeloma cells, (2) erythropoietin deficiency, either an absolute deficiency due to overt renal failure or relative deficiency despite apparently normal kidney function, (3) treatment-induced myelosuppression or myelodysplasia, (4) autoimmune hemolysis, (5) hemodilution, (6) high marrow levels of IL-6 that can suppresses erythropoiesis, and (7) the many usual causes of anemia in individuals of the same demographics as myeloma patients.

The work by Silvestris et al (page 1155) points to yet another mechanism of anemia in MM, one in which Fas ligand (Fas-L) expressed on the surface of myeloma cells triggers programmed cell death of Fas-expressing erythroid progenitors. Myeloma cells, like several other malignant and some normal cells, express Fas-L as a mechanism to escape immune surveillance by Fas bearing T-lymphocytes (Hahne et al, Science 1996;274:1363-1366; Saas et al, J Clin Invest 1997;99:1173-1178). Silvestris et al convincingly demonstrate that erythroid precursors contain the apoptotic machinery necessary to respond to Fas-L and undergo apoptosis both in vitro and in vivo in the presence of myeloma cells. Moreover, they correlate the expression of Fas-L with progressive myeloma, which might help explain why erythropoietin administration often relieves the anemia early in the course of disease but is less effective in end-stage myeloma. Finally, these results bring the anemia of myeloma into closer association with that of the anemia of chronic inflammation and aplastic anemia, where apoptotic responses to IFN-γ appear to play a major pathogenic role (Dai et al, Blood 1998;91:1235-1242; Young and Maciejewski, N Engl J Med 1997;336:1365-1372).

Recognizing that Fas-L is at least in part responsible for anemia in advanced stage myeloma might have therapeutic implications. Multiple malignant and normal cell types express decoy Fas receptors (Pitti et al, Nature 1998;396:699-703; Ohshima et al, Cancer Lett 2000;160:89-97; Jenkins et al, J Biol Chem 2000;275:7988-7993), which by virtue of alterations in the cytoplasmic signaling domain prevent Fas-L–induced apoptosis. It is not a very far leap to envision that the administration of a soluble form of Fas might be able to prevent the suppression of erythropoiesis seen in aggressive multiple myeloma. One need only turn to the success of soluble TNF receptors to find proof of this principle.