Venetoclax dosed at either 400 mg or 800 mg in combination with daratumumab and dexamethasone showed promising preliminary results in a phase 1/2 study.
In patients with t(11;14) relapsed/refractory multiple myeloma (RRMM), venetoclax (Venclexta) at either 400 mg or 800 mg plus daratumumab (Darzalex) and dexamethasone elicited deep durable responses and showed a tolerable safety profile, according to preliminary results of an expansion cohort from a phase 1/2 study (NCT03314181).1
“Venetoclax, daratumumab and dexamethasone, as we previously published, continues to demonstrate safety consistent with a known safety profile with no treatment-emergent deaths,” lead study author Jonathan L. Kaufman, MD, medical director, and section chief of Winship Cancer Institute Ambulatory Infusion Centers, said during a presentation of the data at ASH Annual Meeting 2021. “Venetoclax, daratumumab, and dexamethasone leads to deep responses, including a greater number of patients achieving a (very good partial response) and MRD negativity at least 10 to the minus 5, and to date, the preliminary efficacy continues to be consistent.”
These data that were from part 3 of the phase 1/2 study, while earlier results from part 1 of the study demonstrated that treatment with venetoclax, daratumumab, and dexamethasone (VenDd) was associated with a tolerable safety profile and overall response rate (ORR) of 95.8%.2 Moreover, part 2 of the study showed that Venetoclax plus daratumumab, bortezomib (Velcade; V) and dexamethasone induced a similar safety profile and conferred an ORR of 91.7% in patients with RRMM, regardless of t(11;14) status.2
In part 3, Kaufman and colleagues wanted to analyze the safety and efficacy of venetoclax at 2 different doses — 400 mg and 800 mg — plus daratumumab and dexamethasone. Part 3 also included a group of patients who received DVd to act as a control to help the researchers properly interpret safety and efficacy.
Patients were randomized in a 4:2:5 fashion.
“The initial studies had more patients at the 800-milligram (dose) and we wanted to learn more about the 400-milligram dose in this study, hence the (randomization) numbers,” Kaufman said.
He noted that venetoclax, regardless of the dosing, was given continuously throughout the study, and daratumumab was administered subcutaneously on its regular schedule. Patients also received 40 mg of dexamethasone on a weekly basis. Patients in the bortezomib-included arm received the triplet therapy in regimens previously noted.
Evaluating the safety and efficacy of VenDd at the 400 and 800 mg dosing levels was the primary endpoint of the study.
Enrolled patients had to be aged 18 years or older, have t(11;14) RRMM, an ECOG performance status 0, 1 or 2, be non-refractory to proteasome inhibitors, non-refractory to anti-CD38 antibodies and received at least 1 prior line of therapy including an IMiD. Moreover, enrolled patients had to have standard adequate hematologic, renal and hepatic function.
Patients, however, were excluded from enrollment if they had prior treatment with venetoclax or any other BCL-2 inhibitors, if they had significant peripheral neuropathy, recent autologous transplant, or any allogeneic transplant, prior anti-CD38 therapy within 6 months prior to the first dose of study drug, and depending on the drug, a washout period of other anti-myeloma treatments 2-6 weeks prior to study enrollment.
Although the study accrual is not yet complete, the results presented at ASH included 15 patients in the Ven400Dd arm, 7 in the Ven800Dd arm and 19 patients in the DVd arm. Patients in both the Ven400Dd arm (range, 1-6) and Ven800Dd arm (range, 1-4) had received a median of 1 prior line of therapy, compared with 2 in the DVd arm (range, 1-4).
Kaufman noted that he anticipates that number will be matched by the time study accrual has been completed.
Moreover, 46.7% of the patient’s in the Ven400Dd arm, 28.6% in the Ven800Dd arm and 42.1% in the DVd arm had received a prior stem cell transplantation. Fourteen patients (93.3%) in the Ven400Dd arm, all patients in the Ven800Dd arm and 17 patients (89.5%) in the DVd arm received a prior proteasome inhibitor. All patients in both the Ven800Dd and DVd arm, as well as 93.3% of patients in the Ven400Dd arm, received a prior IMiD.
There have been no treatment-emergent deaths in this portion of the study, and as of the presentation of the data, 14 of the 15 patients in the Ven400Dd arm and all patients in the Ven800Dd arm remain on the study drug. Seven patients in the DVd arm have discontinued treatment, 6 of which were because of disease progression.
Toxicities were similar between the 3 treatment groups, according to Kaufman. All patients in the DVd arm experienced any grade treatment-emergent adverse event (TEAE) compared with 87% in the Ven400Dd group and 86% in the Ven800Dd arm. Some of the most common AEs that occurred in 20% or more of patients included, but were not limited to, insomnia, fatigue and diarrhea.
Similar differences were also observed regarding infections between the three groups. Grade 3/4 infections occurred more often in the Ven400Dd (13%) and Ven800Dd (14%) group than in the DVd (6%) group.
As far as efficacy, the ORR in the venetoclax groups, as Kaufman expressed, were “very high.” Patients in the Ven400Dd group achieved an ORR of 87% compared with 86% in the Ven800Dd group and 63% in the DVd group. Of note, 72% of the responses in the Ven800Dd group were considered VGPRs.
At the time of presentation of the preliminary results, the median time on treatment in the Ven400Dd group was 6.0 months (range, 0.2-16.5), 8.5 months (range, 1.8-15.9) in the Ven800Dd and 3.9 months (range, 0.5-14.8) in the DVd group.
“We are currently in development of a randomized phase 3 study to confirm these preliminary results,” Kaufman concluded.
1. Kaufman JL, Quach H, Baz R, et al. Safety and Preliminary Efficacy from the Expansion Cohort of a Phase 1/2 Study of Venetoclax Plus Daratumumab and Dexamethasone Vs Daratumumab Plus Bortezomib and Dexamethasone in Patients with t(11;14) Relapsed/Refractory Multiple Myeloma. Presented at 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, Georgia. Abstract 817.
2. 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.