Venetoclax Plus Dd and DVd Elicits Deep and Durable Responses in Relapsed/Refractory Multiple Myeloma

Nizar Bahlis, MD

The addition of venetoclax (Venclexta) to daratumumab (Darzalex), bortezomib (Velcade), and dexamethasone (VenDVd) or daratumumab and dexamethasone alone (VenDd) led to a response rate of more than 90% in patients with relapsed/refractory multiple myeloma, which proved durable in the majority of patients, particularly those with t(11;14) translocation, according to findings from a phase 1 study (NCT03314181).¹

The results, which were published in the Journal of Clinical Oncology, demonstrated that the objective response rate (ORR) was 96% (n = 23; 95% CI, 78.9%-99.9%) with VenDd (n = 24), comprising all very good partial responses or better (≥VGPR). In the VenDVd cohort (n = 24), the ORR was 92% (n = 22; 95% CI, 73.0%-99.0%), with a VGPR rate or better of 79%.

Regarding safety, 1 dose-limiting toxicity was reported in the VenDd cohort of grade 3 febrile neutropenia at the expansion-phase dose of 800 mg, which resolved within 4 days of onset.

“VenDd and VenDVd demonstrated tolerable safety and very encouraging efficacy in patients with relapsed/refractory multiple myeloma with approximately 20 months of follow-up. A notably high rate of deep and durable responses was observed with VenDd in heavily pretreated patients with t(11;14),” lead study author Nizar Bahlis, MD, an associate professor of hematology and oncology at the University of Calgary, and co-investigators wrote in the study publication.

Venetoclax is an oral BCL-2 inhibitor that has shown single-agent activity in patients with relapsed/refractory multiple myeloma with t(11;14). Its use in combination with daratumumab, bortezomib, and dexamethasone may lead to synergistic activity.

As such, investigators launched a multicenter, phase 1 trial to study VenDd in patients with relapsed/refractory multiple myeloma with t(11;14) and VenDVd in cytogenetically unselected patients with relapsed/refractory disease.

Eligible patients included those at least 18 years of age with relapsed/refractory multiple myeloma and documented evidence of progression per International Myeloma Working Group (IMWG) criteria on or after their last prior treatment.

Patients must also have had an ECOG performance status between 0 and 2, acceptable laboratory measures, and measurable disease confirmed by central laboratory at screening.

Patients in the VenDd cohort had t(11;14) as determined by fluorescence in situ hybridization and must have received at least 1 prior line of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug. Patients in the VenDVd cohort must have received 1 to 3 prior lines of therapy and could not be refractory to PIs.

In the VenDd cohort, the median patient age was 63 years (range, 51-76). Fourteen patients (58%) had International Staging System (ISS) stage II or III disease, and the median number of prior lines of therapy was 2.5 (range, 1-8).

In the VenDVd cohort, the median patient age was 64 years (range, 41-80). Fourteen patients (58%) had ISS stage II or III disease, and the median number of prior lines of therapy was 1 (range, 1-3).

In the dose-escalation portion of the study, patients received venetoclax once daily at 400 mg. If proven safe after cycle 1, additional patients were enrolled to receive 800 mg of venetoclax once daily.

VenDd was administered in 28-day cycles. Daratumumab was initially given intravenously (IV) at a dose of 16 mg/kg, but the protocol was amended to administer daratumumab subcutaneously (SC) at a dose of 1800 mg. Daratumumab was given weekly for the first 2 cycles, every 2 weeks for cycles 3 through 6, and then every 4 weeks thereafter.

Dexamethasone was given at 40 mg weekly; dose reductions to 20 mg were allowed for patients who were underweight or at least 75 years of age. Dexamethasone was administered IV for the first dose and IV or orally for subsequent doses.

VenDVd was administered in 21-day cycles for cycles 1 through 8 and 28-day cycles thereafter. Daratumumab was given weekly for the first 3 cycles, every 3 weeks for cycles 4 through 8, and every 4 weeks thereafter.

Dexamethasone was given at 20 mg on days 1, 2, 4, 5, 8, 9, 11, 12, and 15 of cycles 1 through 3; days 1, 2, 4, 5, 8, 9, 11, and 12 of cycles 4 through 8; and 40 mg weekly thereafter.

Bortezomib was administered SC at a dose of 1.3 mg/m² or IV on days 1, 4, 8, and 11 of cycles 1 through 8.

Antibiotic prophylaxis was required for patients receiving venetoclax with bortezomib. For all other patients, anti-infective prophylaxis and granulocyte colony-stimulating factor (G-CSF) were recommended, with the stipulation that G-CSF could not be used during cycle 1. Patients could receive immunoglobulin replacement therapy according to institutional guidelines.

The primary end points of the study were expansion-phase dosing, safety, and ORR. Secondary end points consisted of additional safety evaluation, progression-free survival (PFS), duration of response (DOR), time to progression (TTP), and minimal residual disease (MRD) negativity.

Additional results demonstrated that the median PFS was not reached (NR) in both arms. The 18-month PFS rate was 90.5% (95% CI, 67.0%-97.5%) with VenDd vs 66.7% (95% CI, 42.5%-82.5%) with VenDVd.

Moreover, 33% of patients treated with VenDd vs 21% treated with VenDVd achieved an MRD-negative response defined by a sensitivity of less than 10^-5.

The median DOR was NR in both arms; the estimated 18-month DOR was 90.5% (95% CI, 67.0%-97.5%) with VenDd vs 70% (95% CI, 45.1%-85.3%) with VenDVd.

The 18-month TTP rate was 90.5% (95% CI, 67.0%-97.5%) with VenDd vs 66.7% (95% CI, 42.5%-82.5%) with VenDVd. The median overall survival was NR in both cohorts.

Regarding toxicity, 8 patients in the VenDd cohort (33%) and 6 in the VenDVd cohort (25%) had venetoclax dose reductions because of adverse effects (AEs). Six patients (25%) in the VenDd cohort discontinued venetoclax because of AEs (n = 1, melanoma), withdrawn consent (n = 2), progressive disease (n = 2), and opting for autologous transplantation (n = 1).

In the VenDVd cohort, 12 patients (50%) discontinued venetoclax because of AEs (n = 3, one instance each of knee pain, cognitive disturbance, and treatment-related nausea and abdominal pain), withdrawn consent (n = 2), and progressive disease (n = 7).

Common all-grade AEs in the VenDd and VenDVd cohorts, respectively, included diarrhea (63% vs 54%), nausea (50% vs 50%), fatigue (71% vs 25%), and insomnia (42% vs 54%).

Grade 3 or greater AEs were reported in 88% (n = 21) of patients in the VenDd cohort vs 71% (n = 17) in the VenDVd cohort; the most common events were hypertension (17%) and insomnia (25%) with VenDd vs VenDVd, respectively.

One treatment-emergent death was reported in the VenDVd cohort of sepsis in the context of progressive disease. No other infection-related deaths occurred on study with a median follow-up of 20.9 in the VenDd cohort vs 20.4 months in the VenDVd cohort.

Investigators are now enrolling patients with relapsed/refractory disease and t(11;14) in the randomized, open-label phase 2 expansion cohort that will evaluate VenDd with a DVd control arm.

Reference

1. 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. Accessed August 19, 2021. doi:10.1200/JCO.21.00443