Venetoclax Plus Isatuximab and Dexamethasone

Despite recent advances in treating MM that have improved outcomes, patients with this B-cell malignancy inevitably become refractory to therapy, and thus, must rely on additional treatment options for long-term management of their disease.

Venetoclax is an oral BCL-2 inhibitor which has been recently demonstrated to show clinical activity for the treatment of MM. The BCL-2 family of proteins are critical regulators of apoptosis which include both anti-apoptotic (e.g. BCL-2, MCL-1 and BCL-XL) and pro-apoptotic (e.g. BAK and BAX) elements. The upregulation of anti-apoptotic proteins has been reported for most cancers, but high BCL-2 levels have been especially prevalent in human lymphoid malignancies including chronic lymphocytic leukemia, for which venetoclax is currently indicated. BCL-2 is also overexpressed especially in the subset of MM patients with t(11;14) translocations, a cytogenetic abnormality found in approximately 20% of MM patients.

Venetoclax as a single agent has been shown to induce apoptosis not only in human MM cell lines and primary MM tumor cell samples, but also specifically in RRMM patients. Clinical activity with single-agent venetoclax was mostly limited to those with (11;14) translocations, with 12 of 14 responses occurring among patients with that cytogenetic marker in the single-agent clinical trial of this BCL-2 inhibitor for patients with RRMM (#NCT01794520) as reported by Kumar et al.7 Resistance to venetoclax as a single agent has been shown to be mediated by MCL-1, with low BCL-2/MCL-1 ratios indicating resistance and high ratios indicating an increased sensitivity to this BCL-2 inhibitor. Furthermore, MCL-1 silencing was shown to heighten sensitivity to BCL-2 inhibitors, and MM xenograft models co-expressing BCL-2 with MCL-1 were resistant to venetoclax.

The therapeutic landscape of MM has evolved even more with the discovery and validation of monoclonal antibodies in the treatment of MM. The first two monoclonal antibody-based therapies to show promising activity for treating MM patients were elotuzumab, which targets SLAMF7, and daratumumab, which targets CD38. A recent phase 1 study showed high response rates among RRMM patients with t(11;14) who were treated with daratumumab, dexamethasone and venetoclax.2 The most recent addition to the collection of the antibody-based therapies is a humanized IgG1 monoclonal antibody that binds selectively to a unique epitope on the human CD38 receptor, isatuximab (SAR-650984). A dose finding phase 2 trial of isatuximab as a single agent was well tolerated and showed clinical activity for heavily pre-treated patients with RRMM.3 Furthermore, a phase 1b study examining combination therapy consisting of isatuximab with lenalidomide and dexamethasone showed promising activity and good tolerability for heavily previously treated patients with RRMM. Based on the results of two phase 3 studies, the antibody has been FDA-approved in combination with pomalidomide or carfilzomib for treating RRMM patients.

Notably, the investigators reported two cases of patients with RRMM who achieved rapid complete remissions to therapy with venetoclax at low doses (100 mg) in combination with bortezomib, dexamethasone and the anti-CD38 antibody daratumumab after failing multiple treatment regimens including bortezomib, dexamethasone and daratumumab. The investigators have recently reported on a larger retrospective study of RRMM patients receiving this combination. The response rate was 80% among those harboring the t(11;14) marker whereas it was only 31% among those lacking this chromosomal translocation. Responses were observed among patients who failed prior anti-CD38 antibody treatments. These results suggest that low doses of venetoclax may help overcome resistance to other anti-MM agents for the treatment of RRMM patients especially those with the t(11;14) chromosomal marker. Therefore, in this phase 2 trial, The investigators will evaluate the safety and efficacy of isatuximab, venetoclax and dexamethasone for treating patients with RRMM and show the t(11;14) marker.