One study discussed at the ASH meeting involved a regimen consisting of oral MLN9708 administered twice weekly plus lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma. It concludes that the experimental oral proteasome inhibitor MLN9708, which is the first in its class to enter Phase III, has very good response rates in this combination.
(ag) According to Paul G. Richardson, MD, Boston, the study [1] shows that the regimen of MLN9708 plus lenalidomide and dexamethasone generated high response rates. “This is the first time a completely oral combination has been studied in this constellation. The data demonstrate its activity and feasibility.”
MLN9708 is an experimental oral proteasome inhibitor currently being investigated for the treatment of multiple myeloma (MM) and AL amyloidosis. As the first of its kind, it moves into Phase III of the investigation. Preliminary findings from studies presented at ASCO 2012/2013 testing weekly and twice-weekly treatment schedules in patients with refractory/relapsed MM demonstrated “single-agent” activity. In addition, a study from the 2012 ASH Congress already showed an effect in combination with lenalidomide plus dexamethasone in newly diagnosed MM.
Phase 1: 3.0 mg as fixed dose
The primary objective of the Phase I study was to evaluate the safety, tolerability and maximum tolerated dose (MTD) of the combination. Furthermore, the aim was to find out the optimal dosage for the second phase.
Patients received MLN9708 twice weekly at doses of 3.0 or 3.7 mg. The total combination regimen was divided into 16 cycles of 21 days each in both phases. This was followed by maintenance therapy with MLN9708 until disease progression or severe toxicities.
RESULTS: Fourteen patients received MLN9708, half at the 3.0 dose and the other at the 3.7 mg dose. Dose-limiting toxicities (in the form of severe side effects) were not observed during the first cycle in either group, but the lower dose was chosen because of better tolerability and less frequent occurrence of rashes. Thus, 3.0 mg MLN9708 was used in the second phase.
Phase 2: Good response rates, but more side effects
The primary objective of the Phase II study was to investigate response rates and provide further insights into safety and tolerability.
Results: 50 patients took MLN9708 at a dose of 3.0 mg. At the time of data collection (July 2013), the median follow-up time was 6.9 months, and a median of eight cycles had been given.
The overall response rate was 93%, including 67% with very good partial response (VGPR) and 24% with complete response.
The median duration of response was 5.9 months.
The most common adverse events were rash (61%), fatigue and peripheral edema (50%), diarrhea (41%), and peripheral neuropathy (36%).
Twenty-two percent of patients discontinued therapy in favor of autologous stem cell transplantation, 14% did so because of side effects, 5% because of disease progression, and 19% for other reasons.
Fifty-six percent of patients experienced grade 3 adverse effects associated with the combination, but no drug-induced grade 4 adverse effects were observed.
In 58% of cases, the dose of at least one of the three drugs had to be reduced.
The researchers did not attribute one cardio-respiratory death during the study to either MLN9708 or dexamethasone, but suspected a link to lenalidomide.
“So while twice-weekly administration of oral MLN9708 plus lenalidomide and dexamethasone shows good activity in patients with newly diagnosed MM, the rates of rash, peripheral neuropathy, and dose reductions were elevated compared to the other studies with once-weekly administration. In addition, since response rates are about the same as in these studies, once-weekly dosing is reasonable for the upcoming phase 3 trials,” Richardson concluded his presentation.
Source: 55th ASH Annual Meeting, December 7-10, 2013, New Orleans.
Literature:
- Richardson PG, et al: Twice-Weekly Oral MLN9708 (Ixazomib Citrate), An Investigational Proteasome Inhibitor, In Combination With Lenalidomide (Len) and Dexamethasone (Dex) In Patients (Pts) With Newly Diagnosed Multiple Myeloma (MM): Final Phase 1 Results and Phase 2 Data. ASH Abstract #535.
InFo Oncology & Hematology 2014; 2(2): 29-30.
