Effects of Elotuzumab on Soluble SLAMF7 Levels in Multiple Myeloma

Introduction: Elotuzumab is a humanized monoclonal antibody that binds specifically to Signaling Lymphocyte Activation Molecule Family Member 7 (SLAMF7; CS1), a glycoprotein highly expressed on the surface of multiple myeloma (MM) cells and on subsets of immune cells, including natural killer cells. SLAMF7 also exists as a soluble form (sSLAMF7) and has been detected in the serum of patients with MM at statistically significant higher levels than healthy individuals. Although the mechanism of action of elotuzumab involves the direct activation of natural killer cells and the initiation of antibody-dependent cell-mediated cytotoxicity of SLAMF7-expressing myeloma cells, its effects on sSLAMF7 have not been reported. The biological significance of sSLAMF7 has not been described in MM; however, it has been suggested that sSLAMF7 may be associated with disease stage. In order to assess the pharmacodynamic and predictive utility of this biomarker, we investigated levels of serum sSLAMF7 at baseline and on treatment (Cycle 2 Day 1 [C2D1]) across several elotuzumab clinical studies (HuLuc63-1703, CA204-009, and CA204-011) in both smoldering MM and relapsed/refractory MM. Additionally, associations between changes in sSLAMF7 and pharmacokinetic parameters were investigated. Lastly, associations between sSLAMF7 and markers of disease burden were also assessed.

Methods: Two enzyme-linked immunosorbent assays were developed to detect sSLAMF7 in the presence of elotuzumab: the total assay (TA) detected all forms of sSLAMF7 (both unbound and elotuzumab-bound sSLAMF7) and the free assay (FA) detected only unbound sSLAMF7. Serum was collected from peripheral blood before initiation of treatment (C1D1) and during treatment (C2D1) and assessed for levels of sSLAMF7 by the TA and FA. Soluble component (non-cellular) from bone marrow aspirates were obtained prior to any therapy to assess the relationship between concentrations of sSLAMF7 in matched marrow and blood samples.

Results: As previously reported, these data confirm sSLAMF7 expression in patients with MM. The TA demonstrated a significant dose- and time-dependent increase in sSLAMF7 following elotuzumab treatment alone or in combination with either bortezomib/dexamethasone (E-B/d) or lenalidomide/dexamethasone (E-L/d); this increase was not observed in patients treated with bortezomib/dexamethasone (B/d) only. The increase in total sSLAMF7 observed in the TA demonstrated elotuzumab pharmacodynamic specificity and likely reflected stabilization of the protein in the serum. The FA detected a significant decrease in free sSLAMF7 (at C2D1) in both elotuzumab- and non-elotuzumab-treated patients, with the greatest reduction observed in elotuzumab-treated patients. The decrease in free sSLAMF7 detected using the FA, regardless of treatment, suggest the potential use of this biomarker as a surrogate for disease burden. Additionally, the extent of the C2D1 changes in free and total sSLAMF7 following elotuzumab-containing regimens demonstrated a trend for association with increased depth of response (comparing progressive disease/stable disease/minimal response vs partial response vs very good partial response/complete response). Baseline and C2D1 levels of serum sSLAMF7 showed a trend for an inverse relationship with progression-free survival (for E-L/d) but this was not statistically significant. Baseline sSLAMF7 did demonstrate a positive relation with the percentage of bone marrow plasma cells. At C2D1, with the dose of 10 mg/kg, the mean elotuzumab concentration was 337.1 µg/mL (N=38; CV of 51.6%), which was significantly higher than the mean free sSLAMF7 concentration 0.255 ng/mL (N=37; CV of 200%). In addition, E-L/d treatment demonstrated the greatest reduction of free sSLAMF7 (more than 80% of patients treated with E-L/d reached >75% of free sSLAMF7 reduction) compared with that observed for E-B/d and B/d.

Conclusions: Together, these data suggest that sSLAMF7 may be a surrogate marker of disease burden in MM, and early changes in sSLAMF7 may provide an indication of likelihood of response. Additional analysis of sSLAMF7 is ongoing and future studies will help us to further understand the use of this biomarker for prognostic or predictive purposes.

Study supported by: Bristol-Myers Squibb