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MLN9708 May Revolutionize Treatment of Multiple Myeloma

TOP - February 2013 VOL 6, NO 1 published on March 4, 2013 in Hematologic Cancers
Alice Goodman

An investigational oral proteasome inhibitor known as MLN9708 had such promising results in phase 1 and 2 trials that it is currently in phase 3 testing. If results are positive, the drug is expected to be approved as soon as 2014.

MLN9708 is an oral drug taken once weekly, and will be an alternative to bortezomib, the first proteasome inhibitor developed for multiple myeloma. Bortezomib is administered by intravenous infusion or subcutaneous injection. MLN9708 appears to have a more favorable adverse-effect profile than bortezomib; specifically, peripheral neuropathy has been greatly reduced with the oral agent in trials thus far.

To put this into context, bortezomib given intravenously twice weekly has been associated with peripheral neuropathy in 30% to 40% of patients, compared with rates of about 10% to 15% for MLN9708 in preliminary trials.
Shaji Kumar, MD, of the Mayo Clinic, Rochester, Minnesota, presented results of the phase 1/2 trial at the 54th Annual Meeting of the American Society of Hematology (ASH) after a median of 6 cycles of therapy.

The study had 2 parts. Phase 1 enrolled 15 patients and established 4 mg orally once weekly as the maximum tolerated dose of the investigational agent. Phase 2 included 55 patients with newly diagnosed multiple myeloma. MLN9708 4 mg was given on days 1, 8, and 15, in combination with lenalidomide 25 mg once daily on days 1 to 21 and dexamethasone 40 mg on days 1, 8, 15, and 22.

Twenty patients went on to attempt stem-cell harvesting for transplant. The other 30 remained on therapy at the time of ASH.
Minor adverse events were reported in 40% of patients, including fatigue, nausea, and rash. Seven patients discontinued treatment due to adverse events.

The major serious adverse events of grade 3 or higher were gastrointestinal upset and skin rash (about 5% of patients for each adverse event). Two grade 4 events occurred: end-stage renal disease in 1 patient, which was attributed to the disease itself, and deep vein thrombosis in 1 patient. One patient died from pneumonia.

Mild grade 1 neuropathy occurred in 8.45%, and grade 3 neuropathy developed in only 2.07%.
The overall response rate was 92%; 55% had very good partial response and 23% had complete response. Longer treatment increased the depth of response. For those patients who finished 12 cycles of therapy, the complete response rate increased to 67%, while 33% had very good partial response.

Reference
Kumar SK, Berdeja JG, Niesvizky R, et al. A phase 1/2 study of weekly MLN9708, an investigational oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma (MM). Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 332.

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Last modified: April 27, 2020