A Phase II Trial of IPH2101 (anti-KIR mAb) in Smoldering Multiple Myeloma

Abstract 2944

Emerging evidence suggests multiple myeloma (MM) may be susceptible to components of the innate immune system including natural killer (NK) cells. In vitro studies have shown that allogeneic and autologous NK cells have the ability to kill CD138-purified primary MM cells. A recent study focusing on allogeneic hematopoietic stem cell transplantation for MM showed recipients who lacked MHC class I ligands for donor KIR (so called KIR incompatible transplants) had markedly reduced relapse rates, indicating NK cell KIR may exert significant control over clinical NK cell-mediated anti-MM responses. In this two-stage phase II study, we evaluated the response rate, toxicity, pharmacokinetic parameters and biological activity of IPH2101 in smoldering myeloma (SMM). IPH2101 is a fully human IgG4 monoclonal antibody (mAb) that facilitates natural killer (NK) cell-mediated killing of myeloma cells by blocking the interaction of inhibitory killer cell immunoglobin (Ig)-like receptor (KIR) 2D on NK cells with their human leukocyte antigen-C (HLA-C) ligands on target cells. This interim analysis was planned when all patients in the first stage (n=9/21) were recruited.

Nine SMM patients meeting eligibility criteria were prospectively enrolled (median 59 yrs; 8 males and 1 female). Patients received a single dose of IPH2101 1mg/kg by intravenous route every other month (for a total of 6 cycles). A pre-treatment bone marrow biopsy was obtained for confirmation of diagnosis and for correlative studies. Peripheral blood mononuclear cells were obtained on days 1, 8, 18, 22 for cycle one then monthly thereafter for subsequent cycles for correlative studies to assess KIR 2D blockade and the effects of mAb therapy on NK cytotoxic function against K562 cells and MM cells matched for recipient KIR ligands. Routine blood work, serum/urine protein electrophoresis and immunofixation, and serum free light chain assays were conducted monthly. At the end of study, a post-treatment bone marrow biopsy will be obtained for clinical evaluation and correlative studies.

To date, of the 9 patients enrolled on trial, 1 patient has received 5 cycles, 2 patients have received 4 cycles, and 4 patients have received 2 cycles. After an average of 3 (range 2–5) cycles of IPH2101, no patients have yet achieved a 50% reduction of their baseline M-spike (target for the study). Toxicities have been minimal and no grade 3–4 toxicities have been observed to date. Occupancy of KIR2D by IPH2101 has been assessed on peripheral blood NK cells taken at baseline, 24 hrs after the first infusion, and prior to each subsequent infusion using a flow based KIR occupancy assay that measures the binding of a labeled immunofluorescent anti-KIR relative to standard fluorescent beads. The interim results are consistent with a very high KIR occupancy of >90% at 24 hr post the first infusion and the maintenance of a high level of occupancy of available IPH2101 binding sites at 2 months post-infusion. In vitro studies measuring the cytotoxic function of patient's NK cells against K562 cells and KIR ligand matched myeloma cells before and after IPH2101 treatment are ongoing and will be reported at the meeting.

In conclusion, this first interim analysis based on 9 SMM patients treated with IPH2101 are consistent with a very high KIR2D occupancy on NK cells by this mAb up to 2 months post-infusion. To date, none of the patients treated have had 50% reduction of their baseline M-spike. mAb infusions have been well tolerated with no grade 3–4 toxicities observed to date. Updated clinical data and functional in vitro studies measuring the cytotoxic function of patient's NK cells before and after mAb therapy will be presented at the meeting.