Combination Proteasome Inhibitor Therapy

The proteasome inhibitor bortezomib, which primarily targets the chymotryptic-like (CT-L) proteolytic activity of the proteasome, is an effective therapy for patients with relapsed refractory multiple myeloma (MM) and is superior to high-dose dexamethasone therapy for relapsed MM.^1,2  Excitingly, when combined with dexamethasone it has increased frequency and extent of response both before and after high-dose melphalan and autologous stem cell transplantation.³  In older non-transplant patients, initial therapy with bortezomib combined with melphalan and prednisone achieved significant increases in overall and extent of response, associated with prolonged progression-free and overall survival.⁴  More recently, several next-generation proteasome inhibitors have shown promise at overcoming bortezomib resistance in preclinical models and are under clinical evaluation. Carfilzomib more potently inhibits the CT-L proteolytic activity⁵  and is under evaluation in two phase II clinical trials in MM, having shown early signs of responses in phase I studies.^6,7  NPI-0052, a second-generation proteasome inhibitor targeting CT-L, tryptic-like (T-L), and caspase-like (C-L) proteolytic activities,⁸  is also in phase I clinical trial in MM. Finally, CEP-18770, which is also entering clinical trials, is an oral inhibitor of CT-L proteolytic activity.⁹  At present, the qualitative or quantitative extent of proteasome inhibition associated with clinical efficacy in MM remains to be defined.

Conventional therapies for cancer have been combined to both increase tumor-cell cytotoxicity and decrease attendant toxicity, frequently allowing for use of lower doses of therapy. Chauhan and colleagues provide preclinical evidence suggesting that similar principles may also apply with novel targeted therapies. In particular, combining bortezomib with NPI-0052 induced synergistic activity against MM cell lines in the bone marrow milieu in vitro, as well as in vivo in a human plasmacytoma xenograft model. The biologic sequelae triggered by the combination included activation of caspase-8, 9, 3, and PARP; induction of endoplasmic reticulum stress and JNK; suppression of CT-L, C-L, and T-L proteolytic activities; and blockade of NF-κB signaling.

Immunostaining showed growth inhibition, apoptosis, and decrease of human MM cells, as well as decreased associated angiogenesis, in treated mice. Most importantly, these effects were observed when combining these inhibitors, which are inactive when they are used alone, even at low doses. With these low doses, combination therapy was very well tolerated. These studies suggest, as with conventional combination chemotherapy, that combining proteasome inhibitors may enhance efficacy, delay or overcome drug resistance, lessen attendant side-effect profile, and ultimately improve patient outcome in MM.