Novel Proteasome Inhibitor Elicits Response in Multiple Myeloma Patients
NEW ORLEANS—Twice-weekly administration of ixazomib citrate (MLN9708), an oral investigational proteasome inhibitor, is active in patients with newly diagnosed multiple myeloma, final phase 1/2 results reported at the 55th American Society of Hematology Annual Meeting and Exposition.
“However, rates of rash, peripheral neuropathy, and dose reductions appear higher than in the parallel study using weekly MLN9708, with similar response rates and better convenience, supporting use of weekly dosing in ongoing phase 3 trials,” said Paul G. Richardson, MD, of the Dana-Farber Cancer Institute, Boston, MA, in presenting findings from the study, conducted in collaboration with the Multiple Myeloma Research Consortium.
The trial enrolled 64 patients without grade 2 or higher peripheral neuropathy and no prior or concurrent deep vein thrombosis (DVT)/pulmonary embolism. Median age was 63.5 years (range, 34-82 years); 63% were male, and 30%/36%/17% had International Staging System I/II/III multiple myeloma.
The primary objectives of the phase 2 study were to determine the combined complete response plus very good partial response (CR+VGPR) rate and evaluate safety and tolerability. Secondary objectives included overall response rate (≥ PR), time to response, and duration of response (DOR).
In phase 1, patients received MLN9708 3.0 or 3.7 mg on days 1, 4, 8, 11, lenalidomide 25 mg on days 1 to 14, and dexamethasone 20 mg/10 mg (cycles 1 to 8 and 9 to 16) on days 1, 2, 4, 5, 8, 9, 11, and 12 for up to 16 21-day cycles, followed by MLN9708 maintenance (same schedule) until progression or unacceptable toxicity.
“Transplant-eligible patients could undergo stem cell collection after four cycles [or more] and discontinue for autologous stem cell transplantation (ASCT) after eight cycles [or more],” Dr. Richardson said.
In phase 1, 14 patients received MLN9708, seven each at the 3.0 mg and 3.7 mg doses. No dose-limiting toxicities were observed in cycle 1; however, based on overall tolerability and incidence of rash at the 3.7 mg dose, the phase 2 study dose selected was 3.0 mg, and 50 patients were enrolled at this dose.
Median follow-up was 10.9 months and median number of cycles received was nine (range, 1-30 cycles). Seventy-seven percent of patients had received eight cycles or more and 17%, 16 cycles or more. A total of 33% had discontinued treatment in order to undergo ASCT; in addition, 17% had discontinued due to adverse events (AEs); 9% because of progressive disease; and 16% for other reasons. The remaining 25% of patients continued treatment.
In 62 response-evaluable patients, 94% had a partial response or better, which included 76% with VGPR (26% CR, including 19% stringent CR); 61% had 100% decreases in M-protein or serum-free light chain from baseline.
Based on 56 response-evaluable patients treated at the recommended phase 2 dose, preliminary data show deepening responses over the course of treatment, with 93% overall response rates after four cycles and 95% overall.
Median time to first response (≥ PR) was 0.69 months and, to best response to date, 1.96 months. Median DOR to date was 13.8 months, ranging up to 18.8+ months. Most common AEs were rash (50%), peripheral neuropathies (53%), fatigue (48%), peripheral edema (39%), dysgeusia (31%), diarrhea (30%), and insomnia (30%).
Drug-related grade 3 AEs were seen in 56% of patients, including rash (11%), hyperglycemia (9%), pneumonia (7%), and thrombocytopenia, decreased lymphocyte count, hyponatremia, neutropenia, and peripheral neuropathies (5% each). One on-study death occurred, due to cardiorespiratory arrest, which was likely a pulmonary embolism. The investigator considered this death to be unrelated to MLN9708 or dexamethasone, but “probably” related to lenalidomide.
Based on phase 1 preliminary pharmacokinetic data, MLN2238 was absorbed quickly, with a Tmax of 0.5 to 4 hours. Terminal half-life was 2 to 8 days. “Pharmacokinetic data were similar to single-agent twice-weekly dosing studies, suggesting no MLN2238 PK interaction with lenalidomide or dexamethasone,” he said.
These results support the use of weekly dosing in ongoing phase 3 trials, including TOURMALINE-MM1, TOURMALINE-MM2, and TOURMALINE-AL1, Dr. Richardson concluded.