Phase II Study Of The Combination Of MLN 9708 With Lenalidomide As Maintenance Therapy Post Autologous Stem Cell Transplant In Patients With Multiple Myeloma
Authors: Shah Jatin J. , Baladandayuthapani Veera , Weber Donna M. , Thomas Sheeba K. , Alexanian Raymond , Wang Michael , Qazilbash Muzaffar H. , Champlin Richard E , Shah Nina , Bashir Qaiser , Popat Uday R , Nieto Yago , Ahmed Sairah , Parmar Simrit , Orlowski Robert Z. 
Published: October 2019

Abstract

Background
The role of lenalidomide for maintenance after myeloblative therapy and autologous stem cell transplant (ASCT) has been established based on the CALBG 100104 and IFM 2005-02 experience. Continuous low dose lenalidomide demonstrated a significant benefit in progression free survival (PFS), time to progression (TTP) in both trials and the CALBG trial also demonstrated a benefit in early overall survival. The benefit in PFS with lenalidomide is preserved in patients with high risk cytogenetics and in complete remission after ASCT. Proteaseome inhibitors (PI) have been studied after ASCT in a hybrid consolidation/maintenance model with a predefined course of bortezomib-based therapy, which was well tolerated and led to a significant improvement in response rates and in PFS. However long term proteasome inhibitor maintenance therapy has been limited by the route of administration. The combination of PIs and immunomodulatory agents (IMiDs) have a strong preclinical rationale, and their activity has been confirmed with high response rates in various combinations in both newly diagnosed and relapsed/refractory myeloma. MLN9708, an oral PI, may be more convenient as an oral therapy to be studied in the maintenance setting. Here we report preliminary data from a pilot study of the combination of MLN9708 and lenalidomide as maintenance therapy post ASCT.

Methods
This is a single arm phase II study with the primary objective to establish the safety and efficacy (PFS) of MLN 9708 (Ixazomib) and lenalidomide in the maintenance setting post ASCT. The secondary objectives were to evaluate the incidence of secondary primary malignancy, the best response rate (sCR/nCR/VGPR/PR), time to progression and time to next therapy. Patients must have undergone ASCT with melphalan as a preparative regimen within 12 months of initiation of induction for newly diagnosed myeloma. Patients started maintenance therapy 60-180 days post ASCT. Treatment consisted of 28 day cycles of oral MLN9708 4 mg on days 1, 8, 15, and oral lenalidomide 10 mg daily on days 1-28 with a dose increase to 15 mg after 3 months if tolerating well. Adverse events (AEs) were graded by NCI-CTCAE v4. Response was assessed by the modified International Uniform Response Criteria.

Results
A total of 16 patients have been enrolled with a median age of 60 years (range 51-74); 12/16 patients were male. 6 patients had ISS stage 1, 2 patients had stage II, 5 patients had stage III, and 3 had an unknown stage. 14 of the patients remain on trial, 2 patients have discontinued maintenance therapy. 1 patient with high risk disease, including del17p, del 13 discontinued due to rapidly progressive disease during cycle 2; 1 patient discontineud due to hospitalization for bilateral pneumonia. 3 patients had a treatment related SAE including 2 patients with PNA, 1 pt with G2 dehydration requiring hospitalization. 5 patients required a dose reduction in MLN9708 or lenalidomide due to G3/4 thrombocytopenia (n=2); dose delays for thrombocytopenia/neutropenia (n=3); one patient also had concurrent grade 3 rash.
Hematologic toxicity included 3/16 patients with G3/4 thrombocytopenia, 9/16 with G1/2 thrombocytopenia, 5/16 patients with G3 neutropenia and 6/16 patients with G1/2 neutropenia. G3/4 drug-related non-hematologic AEs occurring in >1/16 of patients were limited to 2 patients with G3 creatinine elevation (in the setting of hospitalization for pneumonia). Additional non-hematologic G1/2 events included 9/16 patients with nausea, 5/16 with diarrhea, 9/16 with constipation, 4/16 with emesis, 6/16 patients with G1 rash; 1 pt with worsening of baseline G1 neuropathy.

Conclusions
The combination of MLN9708 and lenalidomide as maintenance therapy post ASCT for NDMM is a well-tolerated combination. 14/16 patients remain on study with only 1 patient discontinuing due to toxicity (pneumonia). The preliminary experience demonstrates the combination is safe, feasible and well tolerated with minimal toxicity and no unexpected toxicity.

Disclosures:
Shah: Celgene: Consultancy, Research Funding; Array: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Off Label Use: This abstract describes bortezomib + rituximab as 1st line induction therapy for patients with Waldenstrom macroglobulinemia. Thomas:Millenium: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Immunomedics: Research Funding; Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees. Wang:Onyx: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Novartis: Research Funding. Qazilbash:Otsuka Pharmaceuticals: Research Funding. Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees.