Efficacy of venetoclax plus anti‐CD38 monoclonal antibody‐containing therapies among t(11;14) positive multiple myeloma patients regardless of timing of prior treatment with this antibody

This study identifies a potential effective therapeutic approach and treatment option for RRMM patients with t(11;14) with prior exposure to anti-CD38 medications and should lead to more extensive evaluation of this combination therapy regardless of time from prior exposure to a CD38 antibody as part of another treatment regimen. Anti-CD38 mAbs are standard treatment options for RRMM patients.1-3 The relationship between the time since treatment with a prior anti-CD38 mAb regimen and the efficacy of another therapy containing these antibodies is limited and has not been reported for a combination containing venetoclax. In a study investigating isatuximab monotherapy for daratumumab refractory MM patients, the disease control rate was greater among those with a time from their last daratumumab to isatuximab of >6 months versus those <3 months.4 Venetoclax, a BCL-2 inhibitor, has shown efficacy for RRMM patients with t(11;14) when combined with bortezomib, dexamethasone, and daratumumab.5-8 This study investigated the relationship between the time since the last anti-CD38 mAb treatment and the efficacy of a venetoclax and anti-CD38 mAb-containing regimen among RRMM patients with t(11;14). All MM patients with t(11;14) who received a venetoclax and an anti-CD38 mAb-containing regimen were identified between January 2017 and April 2022. Those treated with this combination and who had received at least one prior anti-CD38 mAb regimen were included. Patients were excluded if the venetoclax plus anti-CD38 mAb-containing treatment was initiated at another clinic. Among the 11 patients, all received venetoclax with daratumumab, bortezomib, and dexamethasone except for one patient who received this combination without bortezomib. Overall response rate (ORR) and clinical benefit rate (CBR) were 64% (7/11) and 73% (8/11), respectively (Table 1). Among the eight responders (i.e., ≥CBR), the median time between the last anti-CD38 mAb treatment and the venetoclax and anti-CD38 mAb-containing regimen was 25 days (range: 5–239 days). Seven responders initiated the venetoclax plus anti-CD38 treatment <120 days after prior anti-CD38 mAb exposure (Table 1). The only patient who achieved a very good partial response started venetoclax 5 days after failing the prior anti-CD38 treatment (Table 1). Thus, venetoclax plus anti-CD38 mAb-containing regimens are effective for RRMM patients with t(11;14) regardless of the time that elapsed from their previous anti-CD38 mAb exposure as part of another regimen. Compared to our group's prior study investigating multiple exposures to anti-CD38 mAbs, the venetoclax plus anti-CD38 mAb combination in this subpopulation with t(11;14) had a greater ORR (64% vs. 40.8%) and CBR (73% vs. 42.9%) than what we previously reported among all RRMM patients treated with another anti-CD38 mAb-containing combination.9 Furthermore, compared to reports of greater efficacy among patients receiving anti-CD38 mAb regimens after a 6-month washout period from this antibody treatment, all except one responding patient in this study were treated <120 days from prior anti-CD38 mAb treatment.4 This suggests that a 6-month time without exposure to an anti-CD38 mAb is unnecessary for RRMM patients with t(11;14) receiving venetoclax and anti-CD38 mAb-containing therapy. It is possible that venetoclax alone or in combination with bortezomib may have produced the clinical activity as has been previously reported.10, 11 We believe this study warrants further investigation of the combination of venetoclax with an anti-CD38 mAb for RRMM patients with t(11;14) without requiring a specific time to elapse from prior anti-CD38 mAb treatment. James R. Berenson designed the study. Regina Swift collected specimens for analysis. Bernard Sean Regidor, Dilawer Siddiqi, Bethany Marie Beatty, and Marissa-Skye Goldwater generated the data. Bernard Sean Regidor, Dilawer Siddiqi, Bethany Marie Beatty, Scott Jew, Sean Bujarski, Marissa-Skye Goldwater, Susanna Kim, and James R. Berenson organized the data. Bernard Sean Regidor, Scott Jew, Marissa-Skye Goldwater, and Sean Bujarski analyzed the data. Bernard Sean Regidor, Dilawer Siddiqi, Bethany Marie Beatty, Marissa-Skye Goldwater, Susanna Kim, and James R. Berenson wrote the manuscript. The authors thank the patients at Berenson Cancer Center for their contributions to the study and all healthcare professional staff involved in collecting clinical specimens. James R. Berenson receives speaker fees from Janssen and has been on advisory boards with Janssen and Abbvie. All other authors declare that they have no conflict of interest. There was no other funding for this study.