The Hematologist

November-December 2012, Volume 9, Issue 6

Oral Proteasome Inhibitors in Multiple Myeloma

Kenneth C. Anderson, MD Kraft Family Professor of Medicine
Harvard Medical School; Dana-Farber Cancer Institute, Boston, MA

Published on: November 01, 2012

Dr. Anderson has served on advisory boards for Celgene, Millennium: The Takeda Oncology Company, and Onyx.

Study Title: A Phase 3, Randomized, Double-Blind, Multicenter Study Comparing Oral MLN9708 Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in Adult Patients With Relapsed and/or Refractory Multiple Myeloma 

Sponsor: Millennium Pharmaceuticals, Inc. Identifier: NCT01564537

Participating Centers: 8 centers throughout the United States

Accrual Goal: 703 patients

Study Design: An estimated 703 patients with relapsed and/or refractory multiple myeloma (MM) will be enrolled. They must have received one to three prior therapies, have disease that is not refractory to lenalidomide or proteasome inhibitor therapy, and have adequate cardiac, pulmonary, renal, and hepatic function. Patients in the experimental arm will receive MLN9708 (4 mg orally) on days 1, 8, and 15 along with lenalidomide (25 mg) on days 1 through 21 and dexamethasone (40 mg) on days 1, 8, 15, and 22 every 28 days until disease progression. Patients in the placebo comparator cohort will receive a placebo on days 1, 8, and 15 along with lenalidomide (25 mg) on days 1 through 21 and dexamethasone (40 mg) on days 1, 8, 15, and 22 every 28 days until disease progression. Primary endpoint is progression-free survival (PFS), and secondary endpoints include overall survival (OS), rate of complete and very good partial response, duration of response, time to progression, safety profile, pain response, change in global health status, OS and PFS in the high-risk population, and pharmacokinetic data.

Rationale: This clinical trial will compare the PFS in patients with relapsed and/or refractory MM receiving either MLN9708 or placebo, in each case combined with lenalidomide and dexamethasone. Therefore, this clinical trial is a new drug registration trial that attempts to build upon the PFS benefit of lenalidomide in combination with dexamethasone, an FDA-approved regimen in this patient population.

Comment: The use of proteasome inhibitors and immunomodulatory drugs has transformed MM therapy and patient outcome. In particular, the combination of bortezomib and dexamethasone has shown efficacy in the treatment of relapsed, refractory, and newly diagnosed MM. Similarly, the combination of lenalidomide and dexamethasone has shown efficacy in the treatment of relapsed and refractory as well as newly diagnosed MM. Apparently because of synergistic cytotoxicity, the combination of lenalidomide, bortezomib, and dexamethasone can achieve responses in 60 percent of patients whose MM is refractory to either lenalidomide or bortezomib alone. When used as initial therapy, this combination regimen achieves responses universally, with 74 percent of patients having a very good partial response or better and 52 percent having complete and near complete responses, including molecular complete responses. The second generation proteasome inhibitor carfilzomib has recently been approved for treatment of patients who have received at least two prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of completion of the last therapy. Already the combination of carfilzomib, lenalidomide, and dexamethasone has shown remarkable activity in relapsed MM, providing the basis for a recently fully-enrolled phase III clinical trial comparing carfilzomib, lenalidomide, and dexamethasone with the standard lenalidomide/dexamethasone combination. MLN9708 is an oral chymotryptic  proteasome inhibitor, which in preclinical studies triggers activation of caspase 8 and 9, upregulation of p21, induction of ER stress response, downregulation of NF-κB, inhibition of angiogenesis, and activity in a xenograft murine model of human MM. In phase I clinical trials, the maximum tolerated dose (MTD) was established at 4 mg. Neurotoxicity was not observed and adverse effects were minimal (rash, GI toxicity). MLN9708 has a half-life of four to six days and is given either weekly or twice weekly. In early clinical trials, MLN9708 has been combined with lenalidomide/dexamethasone and this combination produced significant responses both in relapsed and newly diagnosed MM. Therefore, this current phase III randomized trial compares combined lenalidomide, dexamethasone, and MLN9708, predicated upon synergistic preclinical cytotoxicity and promising clinical activity, with lenalidomide/dexamethasone for new drug approval in relapsed MM. For the first time, it will define the efficacy and tolerability of an all-oral regimen incorporating immunomodulatory drug and proteasome inhibitor combination therapy. Moreover, although this trial focuses on patients with relapsed MM who have received one to three prior therapies, this combination is also being studied as both initial and maintenance therapy.

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