Update on a Phase II Study of Ixazomib with Lenalidomide As Maintenance Therapy Following Autologous Stem Cell Transplant in Patients with Multiple Myeloma

Background: Maintenance lenalidomide (Len) use in the post autologous stem cell transplant (ASCT) setting has demonstrated a significant benefit in progression-free survival (PFS), time to progression (TTP), and overall survival (OS) in randomized phase III trials. The use of a proteasome inhibitor (PI) as maintenance therapy has been limited by the inconvenience of its IV/subcutaneous administration. Because ixazomib is an oral PI, it may provide an alternative more convenient maintenance therapy option which may improve PFS when combined with Len. Here we report the updated results of a single arm phase II study combining ixazomib and Len as post ASCT maintenance therapy in patients (pts) with newly diagnosed multiple myeloma (NDMM).

Methods: This is a single arm phase II study of the combination of lenalidomide/ixazomib (LenI) maintenance therapy for NDMM pts post ASCT. The primary objective was to establish safety and efficacy of LenI as maintenance therapy. The secondary objectives were to evaluate the incidence of second primary malignancies (SPMs), overall response rate, and toxicity profile. Eligible pts had undergone ASCT with high dose melphalan within 12 months of initiation of induction therapy. Pts were required to start maintenance therapy 60-180 days post ASCT. Treatment consisted of 28-day cycles of ixazomib 4 mg on days 1, 8, 15, and Len 10 mg daily on days 1-28. Len was increased to 15 mg after 3 months if well tolerated. Based on clinical experience from other sponsored studies, the protocol was later amended in August 2013 to reduce the starting dose of ixazomib to 3 mg. Adverse events were graded by NCI-CTCAE v4. Response was assessed by the modified IMWG Uniform Response Criteria.

Results: 64 pts were enrolled with a median age of 60 (range 39-74); 66% (42/64) were male. 32 pts had ISS stage I disease, 13 had stage II; and 9 had stage III. Of the 64 pts, 34 remain on therapy and as of May 2017, they have received a median of 28 cycles (range 1-51). Best overall response include sCR (7.8%), CR (26.5%), VGPR (53%) and PR (10.9%). 29 patients had an improvement in their best overall response from their baseline response. The median PFS still has not been reached with a median follow up of 37.8 months; however, the estimated 2-year PFS is 81%. 20 patients had high risk disease by cytogenetics/FISH; PFS for this subgroup has not been reached yet. 30 pts are off study: 16 due to progressive disease (PD), 3 at PI discretion, and 11 due to consent withdrawal. 8/16 pts with PD had high risk disease; 2/16 had intermediate risk disease. Median PFS post ASCT for these 16 pts was 17 months (3 to 43 months). 7 pts have died with an OS of 4, 16 (2), 20 (2), and 48 (2) months.

Table 1 summarizes significant adverse events. 22 patients had G1/2 peripheral neuropathy (PN); 6 pts had G3 PN. 3 pts had SPMs diagnosed while on maintenance; one patient had DCIS of the breast and two patients had squamous cell carcinoma of the skin.

16 patients started on ixazomib at 4 mg while 48 patients started at 3 mg. 16 patients required a dose reduction to 2.4 mg for PN (8), neutropenia (3), hearing loss (2), rash (1), thrombocytopenia (1). 5 patients required a further reduction in dose to 1.5 mg for neuropathy (3), neutropenia (1) and thrombocytopenia (1). 4 patients discontinued ixazomib for neuropathy (2), neutropenia (1), and thrombocytopenia (1). 15 pts had a dose reduction of Len to 10 mg for 21 of a 28 day cycle, while 9 patients had a dose reduction to 5 mg for 28 days. 1 patient had a dose increase to 15 mg for 28 days, however later this was reduced to 10 mg for 28 days. Reasons for Len dose reduction included neutropenia (12), rash (4), thrombocytopenia (3), fatigue (1), memory impairment (1), infection (1), and pruritis (1). 5 patients required a second dose reduction in Len to 5 mg for 21 days of a 28 day cycle secondary to neutropenia (2), neuropathy(1), thrombocytopenia (1) and fatigue(1).

Conclusions: This updated data establishes that long term administration of combination of LenI as maintenance therapy post ASCT is feasible with pts ongoing at 51+ cycles. The incidence of adverse events was similar to historical experience with Len alone; hematologic adverse events were manageable with dose reductions. The incidence of PN was limited to grade 1/2 events and 6 grade 3 events with no other unexpected toxicity. The combination is safe, feasible, well tolerated and experience to date supports further exploration in phase III studies.

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