ATLANTA — The combination of the investigational weekly oral, proteasome inhibitor, MNL9708, plus standard dose lenalidomide and dexamethasone has antitumor activity at the recommended phase 2 dose in treatment-naïve patients with multiple myeloma, investigators reported at the 54th American Society of Hematology Annual Meeting and Exposition.

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Results from the ongoing phase 2 portion of the phase 1/2 study demonstrated an overall response rate of 90%, with the study meeting its primary endpoint of combined complete and very good partial responses; 58% of patients achieved a very good partial response or greater and 23%, a complete response, results consistent with those reported with the bortezomib, lenalidomide, and dexamethasone (VRD/RVD) regimen, said Shaji K. Kumar, MD, associate professor of hematology and medicine in the Division of Hematology, Mayo Clinic, Rochester, MN, and colleagues.

The phase 1 study was initiated November 2010 and the phase 2, October 2011; at data cut-off, 65 patients were enrolled, 36 male, 15 in phase 1 and 50 in phase 2. Median age was 66 years (range 34–86 years); 43% had ISS stage II and 13%, stage III.

In the phase 1 portion of the study, patients received escalating doses of oral MLN9708 days 1, 8, and 15 plus lenalidomide 25mg days 1–21 and dexamethasone 40mg days 1, 8, 15, 22 for up to twelve 28-day cycles. MLN9708 dose escalation (1.68–3.95mg/m2) proceeded using a standard 3+3 design, based on cycle 1 dose-limiting toxicities. The phase 1 data were reported in a separate presentation during the meeting.

In phase 2, patients received MLN9708 at the recommended phase 2 dose, 4.0mg (after dose conversion), on days 1, 8, and 15 plus lenalidomide and dexamethasone on the same schedule. Patients could undergo stem cell collection after 3 cycles and discontinue for autologous stem cell transplant (ASCT) after 6 cycles.

A total of 53 patients received a median of 7 cycles of therapy (range, 1-19 cycles) at the recommended phase 2 dose of MNL9708 4.0mg. At data cut-off, 52 of 53 patients were evaluable for response and 26 patients remain on therapy. Of the three patients who completed 12 cycles of therapy to date, two achieved a complete response and one, a partial response.

Among patients who achieved a complete response at the recommended phase 2 dose, assessment of minimal residual disease was conducted in eight patients and seven (88%) had negative results.

Treatment-emergent peripheral neuropathy was reported in 21 patients (32%); 13 patients grade 1; six, grade 2; and two patients, grade 3. There was one on-study death.

The most common grade 3/4 adverse events were rash (18%), neutropenia (9%), vomiting (8%), back pain (7%), thrombocytopenia, anemia, fatigue, diarrhea, and hyponatremia (all 6%), and nausea, dehydration, hypokalemia, and hypophosphatemia (all 5%).

Two global phase 3 trials, TOURMALINE-MM1, to investigate MNL9708 in combination with lenalidomide and dexamethasone in relapsed and/or refractory multiply myeloma and TOURMALINE-AL1, to investigate MLN9708 plus dexamethasone in patients with relapsed or refractory light chain AL amyloidosis, were initiated in 2012.

The study was supported by Millennium: The Takeda Oncology Company.


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