Effect of Elotuzumab on Circulating Lymphocytes, Chemokines, and Cytokines In Multiple Myeloma Patients

Abstract 4070

Background: Elotuzumab is a humanized monoclonal IgG1 antibody directed against CS1, a cell surface glycoprotein which is highly and uniformly expressed on malignant plasma cells in multiple myeloma (MM). CS1 is also expressed at a lower level on the cell surface of natural killer (NK) cells, natural killer T-cells (NKT), and on a subset of CD8 positive T-cells, but not resting B cells, monocytes, or CD4 positive T-cells. Preclinical studies have previously demonstrated that elotuzumab kills myeloma cells via NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). In addition, in whole blood assays elotuzumab treatment resulted in the elevation of chemokines and cytokines in culture supernatants. Elotuzumab is being studied in three phase 1 clinical trials in relapsed and/or refractory MM: 1) a monotherapy dose-escalation study, 2) a combination study with bortezomib, and 3) a combination study with lenalidomide and low-dose dexamethasone. Given that NK cells express CS1, there was a concern that elotuzumab treatment could potentially lead to NK cell depletion. Therefore, the pharmacodynamic goals of these clinical studies were to examine the effects of elotuzumab treatment on lymphocyte counts (in particular NK cells), chemokine levels, and cytokine levels. Methods: Absolute lymphocyte counts were determined in peripheral blood samples using the TruCOUNT™ flow cytometry assay. Serum levels of chemokines and cytokines were measured using a multiplex, bead-based assay (Luminex^®). Results: In all 3 studies, we observed no depletion of total lymphocytes or lymphocyte subsets, including CS1 positive NK cells, with elotuzumab dosing either alone or in combination with bortezomib or lenalidomide/dexamethasone. A transient decrease in the absolute number of circulating total lymphocytes (approximately 75%–90% reduction from baseline) upon first elotuzumab dose was observed, followed by a recovery of these lymphocyte counts to baseline or near baseline levels as dosing cycles continued. The transient decrease in lymphocytes included both CS1 positive and CS1 negative cell subsets. This transient decrease in lymphocyte counts was associated with increased levels of circulating chemokines and cytokines following dosing. Post-dose serum samples from study subjects had a median 16-fold (range 1.3–270-fold) elevated levels of interferon inducible protein 10 (IP-10), a chemokine well known to induce lymphocyte trafficking. Other serum analytes were elevated following the initial elotuzumab dosing, including MCP-1, IL-6, and TNF-α, also known for their role in chemotaxis and inflammatory processes. The elevated levels of chemokines and cytokines were generally not seen at subsequent doses. Conclusions: A transient decrease in both CS1 positive and CS1 negative lymphocyte counts was observed following the first dose of elotuzumab in all phase 1 studies in patients with relapsed and/or refractory MM, which resolved during subsequent dosing. This transient decrease appears to be due to lymphocyte trafficking resulting from release of chemokines and cytokines. No evidence of elotuzumab-mediated depletion of CS1 positive lymphocytes was observed. Elotuzumab treatment thus does not appear to be associated with NK cell depletion.