Robust, Long-Lasting Responses Observed With VenDd and VenDVd in the Treatment of Relapsed/Refractory Multiple Myeloma

Patients with relapsed or refractory multiple myeloma with or without t(11;14) experienced promising responses after being treated with venetoclax plus daratumumab and dexamethasone, as well as venetoclax plus daratumumab, dexamethasone, and bortezomib.

High rates of deep and durable responses were observed among patients with relapsed/refractory multiple myeloma with or without t(11;14) translocation who were treated with venetoclax (Venclexta) with daratumumab (Darzalex) and dexamethasone (VenDd) and VenDd with bortezomib (VenDVd), according to data from a phase 1 study (NCT03314181) published in the Journal of Clinical Oncology.

The median follow-up was approximately 21 months (range, 19-30) and 21.5 months (range, 19-26) for patients treated with VenDd and patients treated with VenDVd, respectively. A confirmed response was observed in 96% of patients (n = 23) who were treated with VenDd (95% CI, 78.9%-99.9%), as well as 92% of patients (n = 22) treated with VenDVd (95% CI, 73.0%-99.0%) The rate of complete response (CR) or better was 58% (95% CI, 36.6%-77.9%) and 46% (95% CI, 25.6%-67.2%) for patients treated with VenDd and VenDVd, respectively. All patients also had at least a 50% or higher reduction in serum M-protein levels with very good partial response (VGPR) or better rates of 96% with VenDd (95% CI, 78.9%-99.9%) and 79% with VenDVd (95% CI, 57.8%-92.9%).

“In this study, treatment with VenDd and VenDVd resulted in notable efficacy and acceptable safety in patients with t(11;14) [relapsed/refractory multiple myeloma] and cytogenetically unselected [relapsed/refractory multiple myeloma], respectively,” the investigators wrote. “Although differences in the study population and treatment schedule between the VenDd and VenDVd arms prevent direct comparisons of the two arms, neither combination had new safety signals, and the addition of daratumumab to 800 mg oral daily venetoclax did not appear to alter the known safety profiles of venetoclax or daratumumab combinations.”

Patients were enrolled on the study between April 17, 2018, and March 14, 2019, including 24 patients with t(11;14) relapsed/refractory multiple myeloma in part 1 of the study and 24 patients who were cytogenetically unselected in part 2. Patients in part 1 of the study had a median age of 63 years (range, 51-76) and received a median of 2.5 lines of prior therapy. The median age was 64 years (range, 41-80) with a median of 1 (range, 1-3) prior line of therapy for patients in part 2.

The median time to response was 1 month with VenDd and 0.7 months with VenDVd. The median duration of response, median progression-free survival, and median overall survival were not reached in either arms.

Findings from part 2 of the study highlighted that 83% of patients with t(11;14) relapsed/refractory multiple myeloma responded to VenDVd, as well as 94% of patients without t(11;14). Additionally, 1 patient who had gain(1q) responded to treatment with VenDVd, as well as all patients with high risk cytogenetics (n = 4).

Safety was a key primary end point of the study, with common any grade treatment-emergent adverse effects (TEAEs) including fatigue (71%), diarrhea (63%), nausea (50%), and insomnia (42%). Grade 3 or higher TEAEs were observed in 88% of patients treated with VenDd and 71% of patients treated with VenDVd. Common grade 3 or higher TEAEs included hypertension (17%) and insomnia (25%) for patients treated with VenDd and VenDVd, respectively.

“Given the high response rate and MRD negativity associated with VenDd in patients with t(11;14) [relapsed/refractory multiple myeloma], the phase II portion of this study will enroll patients with t(11;14) [relapsed/refractory multiple myeloma] to a randomized, open-label expansion cohort that will evaluate VenDd with a DVd control arm to contextualize safety results, which could inform the design of a future phase III trial. The results of this study support further exploration of targeting BCL-2 with venetoclax in combination with anti-CD38 immune therapy to treat t(11;14) [relapsed/refractory multiple myeloma],” the investigators concluded.

Reference

Bahlis NJ, Baz R, Harrison SJ, et al. Phase I study of venetoclax plus daratumumab and dexamethasone, with or without bortezomib, in patients with relapsed or refractory multiple myeloma with and without t(11;14). J Clin Oncol. Published online, August 13, 2021. doi:10.1200/JCO.21.00443