Evaluating Venetoclax Plus Daratumumab and Dexamethasone in Relapsed/Refractory MM

Treatment with oral BCL-2 inhibitor venetoclax induced deep and durable responses in patients with relapsed or refractory multiple myeloma (MM), especially those with t(11;14) translocation, according to recent findings published in the Journal of Clinical Oncology.

This phase I study, led by Nizar J. Bahlis, MD, of Arnie Charbonneau Cancer Institute at the University of Calgary in Canada, enrolled 48 patients with relapsed or refractory MM. Patients with t(11;14) translocation received venetoclax in combination with daratumumab and dexamethasone (VenDd), while cytogenetically unselected patients were treated with VenDd plus bortezomib (VenDVd). There were 24 patients in each of the two treatment groups.

Patients receiving VenDd had a median age of 63 years (range = 51-76) and had received a median of 2.5 prior lines of therapy (range = 1-8). Of the 24 patients in this group, 14 (58%) had International Staging System (ISS) stage II or III disease.

In the VenDVd group, patients had a median age of 64 years (range = 41-80) and had received a median of one prior line of therapy (range = 1-3). ISS stage II or III disease was reported in 14 patients (58%).

The primary endpoints of the study were expansion-phase dosing, safety, and overall response rate (ORR). Secondary endpoints included further safety analysis, progression-free survival (PFS), duration of response (DOR), and measurable residual disease (MRD) negativity.

At screening, FISH analysis was performed on CD138-enriched bone marrow aspirates to assess t(11;14) and known prognostic cytogenetic markers in MM. High-risk cytogenetics was defined as the presence of t(4;14), t(14;16), or del(17p).

Patients were initially treated with venetoclax 400 mg once daily. After one cycle, upon determination of acceptable safety, 11 patients receiving VenDd and nine patients receiving VenDVd were enrolled to receive venetoclax 800 mg once daily.

During the first two 28-day cycles of VenDd, daratumumab was administered weekly. For cycles 3 through 6, daratumumab was given every two weeks, then every four weeks thereafter. Initially, daratumumab was administered intravenously (IV), but the study protocol was changed to subcutaneous (SC) daratumumab at 1,800 mg. Patients received dexamethasone at 40 mg weekly, with dose reductions to 20 mg allowed for individuals with low body weights and those age 75 or older. For the first dose, dexamethasone was administered IV, then either IV or orally for subsequent doses.

During cycles 1 through 8, VenDVd was administered in 21-day cycles, followed by 28-day cycles thereafter. For the first three cycles, patients received daratumumab as above, then every three weeks during cycles 4 through 8 and every four weeks beyond. On days 1, 2, 4, 5, 8, 9, 11, 12, and 15 of cycles 1-3 and days 1, 2, 4, 5, 8, 9, 11, and 12 of cycles 4-8, patients received dexamethasone at 20 mg, then 40 mg in subsequent cycles. Patients were given bortezomib at 1.3 mg/m2 SC or IV on days 1, 4, 8, and 11 of cycles 1-8.

Median follow-up was 21 months (range = 19-30) for patients in the VenDd group and 21.5 months (range = 19-26) for patients receiving VenDVd.

In the VenDd arm, the ORR was 96% (all very good partial response or better [≥VGPR]). The ORR in patients treated with VenDVd was 92%, with 79% experiencing ≥VGPR (see FIGURE A).

In both treatment groups, median PFS was not reached. At 18 months, the PFS rate was 90.5% (95% CI 67.0 to 97.5) among patients treated with VenDd and 66.7% (95% CI 42.5 to 82.5) in the VenDVd group. DOR was not reached in either arm, but the estimated 18-month DOR was 90.5% (95% CI 67.0 to 97.5) for patients treated with VenDd and 70% (95% CI 45.1 to 85.3) with VenDVd. Among patients treated with VenDd, 33% achieved an MRD-negative response (<10-5), compared with 21% who received VenDVd (see FIGURE B).

Five out of six patients (83%) in the VenDVd group who had t(11;14) relapsed or refractory MM experienced a response, compared with 94% (n=17) of the 18 patients who did not have t(11;14). All four patients with high-risk cytogenetics in the VenDVd arm and one patient with high-risk cytogenetics in the VenDd arm had a response.

Median time on study was 20.9 months (range = 19.2-30) with VenDd and 20.4 months (range = 6.3-25.7) with VenDVd.

Common adverse events (AEs) reported in patients treated with VenDd and VenDVd included diarrhea (63% and 54%, respectively) and nausea (50% and 50%). Grade ≥3 AEs were reported in 88% of patients who received VenDd and 71% of patients who received VenDVd.

Eight patients in the VenDd group (33%) and six patients in the VenDVd group (25%) had venetoclax dose reductions because of AEs. In the VenDd group, six patients discontinued treatment with venetoclax because of melanoma (n=1), withdrawn consent (n=2), progressive disease (n=2), and opting for autologous transplantation (n=1). In the VenDVd group, 12 patients discontinued venetoclax because of AEs (n=3), withdrawn consent (n=2), and progressive disease (n=7).
One patient in the VenDVd group died from sepsis while in hospice care three weeks after discontinuing treatment because of disease progression.

“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 venetoclax 800 mg day did not appear to alter the known safety profiles of venetoclax or daratumumab combinations,” the authors wrote.

The authors report relationships with AbbVie, which sponsored the study.


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) [published online ahead of print, 2021 Aug 13]. J Clin Oncol. doi: 10.1200/JCO.21.00443.