Bortezomib is a proteosome inhibitor used primarily in the treatment of relapsed myeloma. However, it is increasingly being used in the management of myeloma cast nephropathy (MCN).
Bortezomib binds to, and inhibits the function of, the 26S proteosome in plasma cells. This proteosome ordinarily performs a housekeeping function, degrading ubiquitinylated proteins, and hence clearing the cell of abnormal or misfolded proteins. Inhibition prevents degradation of pro-apoptotic factors and results in programmed cell death. The secretory nature of myeloma cells makes them particularly susceptible to agents which interfere with the ubiquitin pathway. Bortezomib has additional effects on other intracellular signaling systems, such as the NF Kappa B pathway, which may attenuate proximal tubular damage from nephrotoxic monoclonal light chains.
There are now several small case series suggesting bortezomib is efficacious in MCN. One of these reports on 20 patients with relapsed MM and creatinine > 2mg/dL. Renal failure was reversed in 40% in under 3 weeks. Additionally, 50% of patients had a 50% improvement in serum creatinine over the course of one month. Toxicity did not appear to be increased.
Bortezomib is given intravenously and does not require dose reduction in renal impairment. For these reasons, bortezomib is likely to have a particularly important role in the future management of patients with monoclonal Ig-mediated kidney disease.
(Image taken from NEJM June 26 2003 Volume 348; 2597-2598)