By Kenneth Anderson, MD

2008-05-01

Dr. Anderson indicated no relevant conflicts of interest.

Chauhan D, Singh A, Brahmandam M, et al. Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma. Blood. 2008;111:1654-64.

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.

1. Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348:2609-17.
   
   
2. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352:2487-98.
   
   
3. Harousseau JL, Mathiot C, Attal M, et al. VELCADE/Dexamethasone (Vel/D) versus VAD as induction treatment prior to autologous stem cell transplantion (ASCT) in newly diagnosed multiple myeloma (MM): updated results of the IFM 2005/01 trial. Blood (Annual Meeting Abstract). 2007;110:138a.
   
   
4. San Miguel JF, Schlag R, Khuageva N, et al. MMY-3002: A phase 3 study comparing Bortezomib-Melphalan-Prednisone (VMP) with Melphalan-Prednisone (MP) in newly diagnosed multiple myeloma. Blood (Annual Meeting Abstract). 2007;110:121.
   
   
5. Kuhn DJ, Chen Q, Voorhees PM, et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood. 2007;110:3281-90.
   
   
6. Orlowski RZ, Stewart K, Vallone M, et al. Safety and antitumor efficacy of the proteasome inhibitor carfilzomib (PR-171) dosed for five consecutive days in hematologic malignancies: phase 1 results. Blood (Annual Meeting Abstract). 2007;110:127a.
   
   
7. Alsina M, Trudel S, Vallone M, et al. Phase 1 single agent antitumor activity of twice weekly consecutive day dosing of the proteasome inhibitor carfilzomib (PR-171) in hematologic malignancies. Blood (Annual Meeting Abstract). 2007;110:128a.
   
   
8. Chauhan D, Catley L, Li G, et al. A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. Cancer Cell. 2005;8:407-19.
   
   
9. Piva R, Ruggeri B, Williams M, et al. CEP-18770: A novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib. Blood. 2008;111:2765-2775.

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