Phase II Study of the Combination of Ixazomib with Lenalidomide As Maintenance Therapy Following Autologous Stem Cell Transplant in Patients with Multiple Myeloma

Background:  The role of maintenance lenalidomide (Len) in the post autologous stem cell transplant (ASCT) setting has been based on a significant benefit in progression-free survival (PFS) and time to progression (TTP) in the CALBG 100104 and IFM 2005-02 trials, and overall survival (OS) benefit in the CALBG100104 trial.  To date, the use of a proteasome inhibitor (PI) as maintenance therapy has been limited by the inconvenience of its IV/subcutaneous administration.  Ixazomib, an oral PI, may provide an alternative maintenance therapy. Here we report the results of a single arm phase II study combining ixazomib and lenalidomide as post ASCT maintenance therapy in patients with newly diagnosed multiple myeloma (NDMM). 

Methods:  This is a single arm phase II study of the combination of lenalidomide/ixazomib (LI) maintenance therapy for NDMM paients post ASCT.  The primary objective was to establish safety and efficacy of Len as maintenance therapy.  The secondary objectives were to evaluate the incidence of secondary primary malignancies (SPMs), overall response rate (sCR/nCR/VGPR/PR), TTP, time to next therapy, and toxicity profile.  Eligible patients had undergone ASCT, with melphalan as a preparative regimen, within 12 months of initiation of induction therapy.  Patients 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 lenalidomide 10 mg daily on days 1-28.  Len was increased to 15 mg after 3 months if well tolerated.  Based on clinical experience from ongoing phase III studies, the protocol was later amended to reduce the starting dose of ixazomib to 3 mg. Adverse events were graded by NCI-CTCAE v4.  Response was assessed by the modified International Uniform Response Criteria.

Results:  65 patients (pts) were enrolled with a median age of 60 (range 39-74); 65% (42/65) were male.  39 pts had ISS stage I disease, 13 had Stage II; and 13 had stage III.  Of the 65 pts, 47 remain on therapy and as of June 2015, pts have received a median of 10 cycles (range 1-30).  The median PFS has not been reached however, the estimated 2-year PFS was 83%.  18 pts are off study: 7 due to progressive disease (PD), 3 at PI discretion, and 8 due to consent withdrawal.  6/7 pts with PD had high risk disease and received 2, 5, 7, 7, 9, 11, and 24 cycles of study therapy.  Among the 7 pts with PD, the median PFS post ASCT was 13 months (6-34 months); 3 pts have died with an OS of 15, 27 and 31 months. 

Grade 3/4 hematologic adverse events (AEs) included: grade 3 (G3) anemia (2), G3 neutropenia (13), G4 neutropenia (2); and G3/4 thrombocytopenia (7).  Grade 3/4 drug-related non-hematologic AEs included: G3 elevated aspartate aminotransferase (3); G3 back pain (2); G3 constipation (4); G3 creatinine increase (2); G3 nausea and diarrhea (2); G3 fatigue (4).  10 pts had G1/2 rash and 8 pts had G3 rash.  42 patients had G1/2 peripheral neuropathy (PN); 1 pt had G3 PN; and 2 pts had G3/4 respiratory failure.  There were no second primary malignancies.

Infectious complications included G3 urinary tract infections (2); G3/4 upper respiratory tract infections (4); G3 sinusitis (1); G3 pneumonia (7); G3 influenza (2); G4 infection (1).  Other AEs included G4 renal failure due to progressive disease (1); G3 non cardiac chest pain (1); G3 emesis (1); G4 respiratory failure and G4 sepsis/respiratory failure (2).

10 patients required a dose reduction of ixazomib for PN (5); neutropenia (3); thrombocytopenia (1), and hearing loss (1).  1 pt discontinued ixazomib and remained on Len due to persistent PN.  11 pts had a dose reduction in Len to 10 mg for 21 of a  28 day cycle due to cytopenias (neutropenia or thrombocytopenia); 5 pts had a dose reduction to 5 mg due to rash/pruritus in 4 pts and 1 pt due to neutropenia.

Conclusions:  Long term administration of combination of lenalidomide/ixazomib as maintenance therapy post ASCT is feasible with pts ongoing at 30+ cycles.  The incidence of adverse events was similar to historical experience with lenalidomide alone; hematologic adverse events were manageable with dose reductions.  The incidence of PN was limited to grade 1/2 events and 1 grade 3 event with no other unexpected toxicity.  The combination is safe, feasible, well tolerated and experience to date supports further exploration in phase III studies.