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SummaryWeekly ixazomib with lenalidomide‐dexamethasone (Rd) is feasible and has shown activity in newly diagnosed multiple myeloma (NDMM) patients. This phase 1/2 study (NCT01383928) evaluated the recommended phase 2 dose (RP2D), pharmacokinetics, safety and efficacy of twice‐weekly ixazomib plus Rd in NDMM; 64 patients were enrolled across both phases. Patients received twice‐weekly oral ixazomib 3·0 or 3·7 mg plus lenalidomide 25 mg and dexamethasone 20 mg (10 mg in cycles 9–16) for up to sixteen 21‐day cycles, followed by maintenance with twice‐weekly ixazomib alone. No dose‐limiting toxicities were reported in cycle 1; the RP2D was 3·0 mg based on overall tolerability across multiple cycles. In 62 evaluable patients, the confirmed overall response rate was 94% (68% ≥very good partial response; 24% complete response). Median progression‐free survival was 24·9 months. Responses (median duration 36·9 months for patients receiving the RP2D) deepened during treatment. Grade 3 drug‐related adverse events (AEs) occurred in 64% of patients, including: rash, 13%; peripheral neuropathy, 8%; hyperglycaemia, 8%. There were no grade 4 drug‐related AEs. Thirteen patients discontinued due to AEs. Twice‐weekly ixazomib‐Rd offers substantial activity with promising long‐term outcomes in NDMM patients but may be associated with greater toxicity compared with weekly ixazomib‐Rd in this setting.

Background MLN9708 (ixazomib citrate) is an oral proteasome inhibitor that is being investigated in phase 3 trials. MLN9708 rapidly hydrolyzes to the biologically active form, MLN2238 (ixazomib). Preliminary findings from studies using weekly and twice-weekly schedules in relapsed/refractory MM have suggested evidence of single-agent activity (Kumar et al, ASCO 2013; Lonial et al, ASCO 2012), and a phase 1/2 study has suggested the feasibility and activity of weekly oral MLN9708 plus len-dex in newly diagnosed MM (Kumar et al, ASH 2012). Here we report the results of a phase 1/2 study, conducted in collaboration with the Multiple Myeloma Research Consortium, of twice-weekly oral MLN9708 plus len-dex (NCT01383928). Methods Phase 1 primary objectives were to determine safety, tolerability, the MTD, and the recommended phase 2 dose (RP2D); secondary objectives included characterizing MLN2238 pharmacokinetics (PK). Phase 2 primary objectives were to determine the combined CR+VGPR rate and further evaluate safety and tolerability; secondary objectives included overall response rate (≥PR), time to response, and duration of response (DOR). Pts aged ≥18 yrs who had no grade ≥2 peripheral neuropathy (PN) and no prior/concurrent DVT/pulmonary embolism received MLN9708 3.0 or 3.7 mg (d 1, 4, 8, 11), len 25 mg (d 1–14), and dex 20/10 mg (cycles 1–8/9–16; d 1, 2, 4, 5, 8, 9, 11, 12) for up to 16 21-day cycles, followed by MLN9708 maintenance (same schedule) until progression or unacceptable toxicity. Transplant-eligible pts could undergo stem cell collection after ≥4 cycles and discontinue for ASCT after ≥8 cycles. Responses were assessed per IMWG uniform response criteria. Adverse events (AEs) were graded per NCI-CTCAE v4.03. Blood samples for PK analysis were taken at multiple time points during cycles 1 and 2. Results 64 pts were enrolled; median age was 64 yrs (range 34–82), 63% were male, and 31%/16% had ISS stage II/III MM. In phase 1, 14 pts received MLN9708 3.0 mg (n=7) and 3.7 mg (n=7). No DLTs were seen in cycle 1; based on overall tolerability and incidence of rash at 3.7 mg, the RP2D was chosen as 3.0 mg. 50 pts were enrolled at this dose in phase 2. At data cut-off (July 1, 2013), the median follow-up was 6.9 months and median number of cycles received was 8 (range 1–26); 73% had received ≥8 cycles and 9% had received ≥16 cycles. At data cut-off, 22% of pts had discontinued to undergo ASCT (median CD34+ stem cell yield 14.9 x 106/kg [range 7–52 x 106]), a further 14%, 5%, and 19% had discontinued due to AEs, progressive disease, and other reasons, respectively, and the other 41% remained on treatment. In 58 response-evaluable pts, ≥PR rate to date was 93%, including 67% ≥VGPR (24% CR, including 14% sCR). 54% of pts had 100% decreases in M-protein or serum free light chain from baseline. Analysis of minimal residual disease is ongoing; data will be presented. Depth of response increased over the course of treatment; median time to first response (≥PR) was 0.69 mos and to best response to date was 2.07 mos. Median DOR to date was 5.9+ mos, ranging up to 18+ mos. Most common AEs were rash (61%; pooled high-level terms), fatigue, peripheral edema (each 50%), diarrhea (41%), and neuropathy peripheral (36%). Drug-related (to any drug in the regimen) grade 3 AEs were seen in 56% of pts, including rash (16%), hyperglycemia (8%), pneumonia (6%), and PN (5%; high-level term). No drug-related grade 4 AEs were seen; 58% of pts required dose reductions of at least one drug due to AEs including rash (16%), anxiety (11%), and PN (8%). AEs resulting in discontinuation were seen in 11%, with the majority reported as not related to therapy. There was 1 on-study death due to cardio-respiratory arrest, likely a pulmonary embolism, considered by the investigator to be unrelated to MLN9708 or dex, but probably len. Based on phase 1 preliminary PK data, MLN2238 was absorbed quickly with a Tmaxof 0.5–4 hours. Terminal half-life was 2–8 days. PK data were similar to single-agent twice-weekly dosing studies, suggesting no MLN2238 PK interaction with len or dex. Conclusions These data suggest that twice-weekly oral MLN9708 plus len-dex is feasible and active in pts with newly diagnosed MM. However, rates of rash, PN, 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. Disclosures: Richardson: Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Investigational agent MLN9708 in combination with lenalidomide and dexamethasone for the first-line treatment of patients with multiple myeloma. Hofmeister:Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Rosenbaum:Janssen: Membership on an entity’s Board of Directors or advisory committees; Celgene: Speakers Bureau. Vesole:Millennium: The Takeda Oncology Company: Speakers Bureau; Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Onyx Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Liedtke:Celgene: Research Funding; Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Chari:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees; Onyx Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees. Lebovic:Celgene: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees. Berg:Millennium: The Takeda Oncology Company: Employment. Liao:Millennium: The Takeda Oncology Company: Employment. Gupta:Millennium: The Takeda Oncology Company: Employment. Di Bacco:Millennium: The Takeda Oncology Company: Employment. Estevam:Millennium: The Takeda Oncology Company: Employment. Hui:Millennium: The Takeda Oncology Company: Employment. Baz:Celgene: Research Funding; Millennium: The Takeda Oncology Company: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Sanofi: Research Funding; Karyopharm: Research Funding.