Expert Point of View: Next-generation Proteasome Inhibitors Will Improve Outcomes in Bortezomib-refractory Myeloma Patients

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Myeloma experts agree that the new proteosome inhibitors are particularly welcome because they are at least as effective as bortezomib (Velcade) but produce much less neuropathy.

Dramatic Results

3.3s.21_richardson.jpg“The activity of MLN 9708 is very encouraging,” said Paul G. Richardson, MD, of Dana-Farber Cancer Institute, Boston. “Upfront we have seen 100% response rates in combination with lenalidomide and dexamethasone, including some very good partial and complete responses. In the relapsed setting we are also seeing single-agent activity, which is promising, as this setting is where we might expect to see much less [activity].1 This signal, in fact, is most promising with the twice-a-week dosing in the advanced disease setting. Also, the main side effect is not neuropathy, but some mild to moderate skin rash, which has proven generally to be manageable. For example, my relapsed patients who participated in the study and who were veterans of neuropathy from exposure to prior bortezomib did not find the skin issue to be a significant problem.”

Meanwhile, carfilzomib is the next-generation proteasome inhibitor expected to gain FDA approval soon, and while “it’s a great drug and is associated with less neurotoxicity, its delivery is inconvenient for patients,” Dr. Richardson maintained. “You must give carfilzomib intravenously weekly, 2 days in a row, on days 1 and 2, 8 and 9, and 15 and 16. MLN9708 has the advantage of being an oral drug, which is convenient, and one that also produces very little neuropathy,” he noted.

Dr. Richardson said he is also impressed with marizomib, though it too is administered twice a week.2 Marizomib is an irreversible proteasome inhibitor, which gives it more potency but perhaps more side effects, including mild (reversible) cognitive dysfunction with the higher dose.

“In patients who have received prior bortezomib, there is a consistent signal. You don’t lose evidence of responsiveness. We think the real benefit will emerge in a combination strategy,” he said. “Marizomib is also exciting for the general oncology community because it crosses the blood-brain barrier and therefore may be effective in brain tumors. Heretofore, no other proteasome inhibitor has done that.”

“MLN 9708, carfilzomib, and marizomib should provide a tremendous platform going forward,” Dr. Richardson said. All the proteasome inhibitors have distinctly different properties, which means “they should all find their place in the treatment of myeloma,” he predicted.

“We need many drugs to prolong the lives of these patients. What we increasingly see is the use of biologically determined treatment,” Dr. Zweegman added.

Postinduction Measures

Clinicians will aim for a complete response with induction therapy. Then, based on the remission status of the patient, a second or perhaps third drug will be added to control disease, she predicted. “We won’t stop with a partial response but will continue treating, and it will be helpful to have new classes of agents. It will also help to have a biologic determination of the malignant plasma cells, and a predictive model for selecting the most appropriate treatment for a given patient.” ■

Disclosure: Dr. Richardson has served on advisory boards for Celgene, Millennium, Novartis, and Bristol-Myers Squibb.


1. Richardson PG, Baz R, Wang L, et al: Investigational agent MLN9708, an oral proteasome inhibitor, in patients with relapsed and/or refractory multiple myeloma: Results from the expansion cohorts of a phase I dose-escalation study. 53rd American Society of Hematology Annual Meeting. Abstract 301. Presented December 12, 2011.

2. Richardson PG, Spencer A, Cannell P, et al: Phase 1 clinical evaluation of twice-weekly marizomib (NPI-0052), a novel proteasome inhibitor, in patients with relapsed/refractory multiple myeloma. 53rd American Society of Hematology Annual Meeting. Abstract 302. Presented December 12, 2011.

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