Prognostic staging in myeloma: in search of biology

For 30 years, clinicians relied on the Durie-Salmon staging system (Durie and Salmon, Cancer. 1975;36:842-854) to define risk in multiple myeloma (MM). In recent years the β₂-microglobulin (β₂M) and C-reactive protein (CRP) have added to the prognostic arsenal (Bataille et al, Blood. 1992;80:733-737). Despite their longevity, both staging systems are limited by an inability to segregate risk accurately in all cases, a particular problem in such a heterogeneous disease. Indeed, until recently prognostic prediction has been something of an irrelevance since all patients with symptomatic disease received essentially the same therapy. Lately, however, the landscape has changed and identification of accurate prognostic biomarkers has assumed increasing importance since therapeutic options may now vary widely according to disease biology.

In this issue, Terpos and colleagues (page 1064) take a step in this direction by examining the roles of the receptor activator of nuclear factor κB ligand (RANKL) and RANK/osteoprotegerin (OPG), which play a dominant role in osteoclast activation and probably in the bone disease common to MM patients (Mundy, Nat Rev Cancer. 2002;2:584-593). The authors demonstrate that in 121 MM patients serum levels of sRANKL were elevated and correlated with bone disease. The sRANKL/OPG ratio was also increased and correlated with markers of bone resorption, osteolytic lesions, and markers of disease activity. More impressively perhaps, sRANKL/OPG ratio, CRP, and β2M were the only independent prognostic factors in multivariate analysis and, used together, defined a low-risk group having a 96% probability of survival at 5 years, as compared with 52% and 0% for the intermediate- and high-risk groups, respectively: a remarkable discriminatory power. The results suggest that the RANKL/OPG system is not only associated with MM bone disease but also impacts the biology of plasma cell growth as reflected by its influence on survival.

Predicting prognosis and defining therapy using novel biomarkers (as described herein), chromosome translocation status and gene expression profiles point the way to the future of MM care, but all require further study. Until confirmed in large prospective studies, user-friendly and sensitive prognostic tools such as the recently devised MM International Staging System (ISS), which employs β2M and albumin, deserve wide implementation, albeit with future refinement (Greipp et al, Hematol J. 2003;4:S42-S44).