Phase 1 Study of Elotuzumab and Peripheral Blood Mononuclear Cell Reconstitution in Combination with Autologous Stem Cell Transplantation and Lenalidomide Maintenance for Multiple Myeloma

Introduction: Elotuzumab is a humanized IgG kappa monoclonal antibody against SLAMF7 that is approved in combination with lenalidomide and dexamethasone for relapsed myeloma. This agent promotes antibody-dependent, cell-mediated cytotoxicity (ADCC) and activation of natural killer (NK) cells to kill tumor cells through ligation of the target. We hypothesized that the addition of elotuzumab and autologous peripheral blood mononuclear cell (PBMC) infusion (to provide NK cells post-transplant) to standard-of-care autologous hematopoietic stem cell transplantation (ASCT) and lenalidomide maintenance for consolidation therapy in myeloma patients will be safe and feasible. This strategy may target residual disease and promote adaptive anti-myeloma immunity, resulting in long-term maintenance of a minimal disease state.

Methods. The primary objective of this Phase 1b, open-label, trial is to assess the safety and efficacy of elotuzumab and autologous PBMC in conjunction with high-dose melphalan and autologous CD34+ stem cell transplantation followed by elotuzumab and lenalidomide maintenance. The secondary objectives are to assess myeloma disease status and progression-free survival (PFS) after one year of treatment. Subjects must have achieved a partial response or better by IMWG criteria with induction chemotherapy, be eligible for ASCT by institutional standards, and meet inclusion/exclusion criteria. Fifteen subjects are planned. Subjects undergo standard peripheral blood stem cell mobilization and harvest, and steady-state leukopheresis for PBMC collection. Subjects receive standard melphalan conditioning (day -1) and autologous stem cell rescue (day 0). Autologous PBMC are reinfused on day +3 and cycle 1 of elotuzumab 20 mg/kg IV is given on day +4. Subjects receive subsequent cycles of elotuzumab every 28 days up to cycle 12. Lenalidomide maintenance at 10 mg orally daily days 1-21 of every 28-day cycle begins with cycle 4 of elotuzumab, and may continue off study beyond cycle 12 at the investigator's discretion. Bone marrow aspirates and peripheral blood are collected for correlative studies at screening, cycle 2, cycle 4, and at the end of study after cycle 12. For the primary endpoint analysis, the safety population includes all subjects who received at least one dose of study treatment. The evaluable population constitutes all subjects who received at least four of the first five planned doses of elotuzumab.

Results: The study completed accrual of the planned 15 subjects, all of whom are included in the safety population and are evaluable. Demographic and staging data reflect the general patient population at our institution. Subjects received 1-2 lines of induction therapy. The majority of adverse events, including infusion reactions attributable to elotuzumab, were grade 2 or lower. Grade 3 or higher hematologic AEs, including anemia, neutropenia, lymphopenia, thrombocytopenia, and non-hematologic AEs including nausea, vomiting, and dehydration, were attributable to the ASCT procedure. One subject demonstrated a delay in hematopoietic reconstitution, which resulted in hospitalization greater than the expected 21 days. Only one subject experienced neutropenic fever during the ASCT admission. One episode of grade 3 hypertension was attributed to elotuzumab infusion and resolved with supportive care. No AEs were attributed to PBMC administration. Two subjects came off study before completion; one for personal choice (VGPR at time of study withdrawal) and one for early progression.

Thirteen subjects completed the study protocol. At one-year post-ASCT, subjects were re-staged and the results are as follows: 1 PR, 6 VGPR, and 7 sCR. ORR was 93% (14/15) and one-year PFS was 93% (14/15). Eleven of 13 subjects who completed the study protocol continued on lenalidomide maintenance. Two subjects (one VGPR and one PR) elected to pursue further consolidation with combination chemotherapy. Correlative studies including tumor microenvironment immunophenotyping, MRD assessment, and T cell receptor sequencing will be presented.

Conclusions: Elotuzumab and PBMC administration with standard ASCT and lenalidomide maintenance for consolidation therapy of multiple myeloma is safe and feasible. One-year disease status, PFS data, and safety profile suggest this protocol compares favorably to standard ASCT consolidation and merits further investigation for efficacy.