In patients with relapsed/refractory multiple myeloma with t(11;14), Selinexor plus venetoclax induced decreases in cyclin D1, XPO1, and MCL-1.
In heavily pretreated relapsed/refractory multiple myeloma cell lines with t(11;14), selinexor (Xpovio) combined with venetoclax (Venclexta) demonstrated efficacy and tolerability, according to small study results that were presented during the 2021 ASH Annual Meeting.
Findings of 6 cell lines presented during the session showed that there is synergy with the combination in myeloma cell lines that possess t(11;14) and that, in these lines, cyclin D1, a known cargo protein of XPO1, was significantly decreased. MCL-1 levels increased; however, the addition of selinexor served to curb this effect.
“Our objectives [were] to investigate the underlying molecular mechanisms that are responsible for the activity of selinexor, venetoclax, and the combination in both t(11;14) and non–t(11;14) myeloma cell lines,” Nina Nguyen, MD, of Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, during a poster presentation of the findings. “Ultimately, with this work, we would like to improve outcomes of [patients with] relapsed/refractory myeloma with t(11;14) by showing that the concomitant administration of selinexor and venetoclax can be safe and effective.”
Researchers initially assessed 2 patients with t(11;14) multiple myeloma who were treated with concomitant therapy; 1 was a 58-year-old Black man, while the other was an 81-year-old White woman. Both patients had progressed through multiple lines of therapy before study initiation, including prior treatment with venetoclax, but both had developed resistance and progressive disease. Both patients responded to the combination of selinexor and venetoclax with a very good partial response and molecular response, respectively.
In the poster, researchers depicted data for 2 cell lines; RPMI-8226, which is a non–t(11;14) cell, and U266-B1, which is a t(11;14) cell line, in a Western blot Analysis.
Notably, cyclin D1 levels in t(11.14) multiple myeloma cell lines were reduced with selinexor, and this decrease was more pronounced with the addition of venetoclax. XPO1 and MCL-1 levels also showed more significant decreases with the drug combination in U266-B1.
Researchers used the CellTiter-Glo assay in multiple myeloma lines with t(11;14) with U266-B1, KMS-12-GM, and SK-MM2, and without t(11;14) in RPMI-8226, LP-1,and OPM-2, with increasing concentrations of selinexor and venetoclax as single agents, and a combination of the 2 drugs. The Bliss Independence model and Synergy Finder rwere used to calculate contour plots.
Overall synergy scores revealed that the cell line U266-B1 with t(11;14) had a stronger response than RPMA-82 [non-t(11;14)] to the combined agents compared with either selinexor or venetoclax as a singular agent.
“In conclusion, selinexor and venetoclax can be administered in patients safely and with response even when patients have previously been exposed to venetoclax,” Nguyen said. “The synergistic mechanism of the drug combination is selective preference and t(11;14) myeloma will be further investigated in a phase 2 clinical trial with preplanned correlative analysis.”