Shaji K. Kumar, MD

As reported in The Lancet Oncology by Shaji K. Kumar, MD, of the Division of Hematology, Mayo Clinic, Rochester, and colleagues, the phase III BELLINI trial has shown that the addition of venetoclax to bortezomib/dexamethasone significantly prolonged progression-free survival in patients with relapsed or refractory multiple myeloma but was associated with increased mortality.¹ The excess mortality reflected a higher incidence of fatalities related to infections.

Study Details

In the double-blind trial, 291 patients from 90 sites in 16 countries were randomly assigned 2:1 between July 2016 and October 2017 to receive venetoclax plus bortezomib/dexamethasone (venetoclax group, n = 194) or placebo plus bortezomib/dexamethasone (control group, n = 97). Randomization was stratified by previous exposure to a proteasome inhibitor and the number of previous therapies. Patients received venetoclax at 800 mg or placebo daily; bortezomib at 1.3 mg/m² subcutaneously (preferred) or intravenously on days 1, 4, 8, and 11; and dexamethasone at 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of 21-day cycles for cycles 1 to 8. From cycle 9 on, bortezomib was given on days 1, 8, 15, and 22 and dexamethasone, on days 1, 2, 8, 9, 15, 16, 22, and 23 of 35-day cycles until disease progression or unacceptable toxicity. The dose of venetoclax could be reduced stepwise to 600 mg, 400 mg, and 200 mg daily. Patients had received one to three prior therapies and had an Eastern Cooperative Oncology Group performance status of up to 2. The primary endpoint was progression-free survival as assessed by an independent review committee in the intention-to-treat population.

For the venetoclax vs control groups, median patient age was 66 vs 65 years (56% vs 54% ≥ 65 years) and 50% vs 57% were male. International Staging System stage was 1 in 42% vs 49%, 2 in 36% vs 33%, and 3 in 20% vs 13%. Overall, 53% vs 55% had received two or three prior lines of therapy; 30% vs 30% were naive to proteasome inhibitors and 70% vs 70% were sensitive; and 68% vs 67% had exposure to immunomodulatory drugs.

Efficacy Outcomes

At the median follow-up of 18.7 months (interquartile range = 16.6–21.0 months), median progression-free survival was 22.4 months (95% confidence interval [CI] = 15.3 months to not estimable) in the venetoclax group vs 11.5 months (95% CI = 9.6–15.0 months) in the control group (hazard ratio [HR] = 0.63, 95% CI = 0.44–0.90, P = .010).

Results were assessed according to several stratification subgroups. For example, among patients who had received a prior proteasome inhibitor, median progression-free survival was 22.4 in the venetoclax group vs 12.6 months in the placebo group (HR = 0.75, 95% CI = 0.48–1.16). Among those without prior exposure to a proteasome inhibitor, progression-free survival was not reached in the venetoclax group vs 10.2 months in the placebo group (HR = 0.46, 95% CI = 0.24–0.88).

Among those who had received one prior line of therapy, progression-free survival was 22.4 in the venetoclax group vs 11.4 months in the placebo group (HR = 0.75, 95% CI = 0.45–1.26). Among those who had received two or three prior lines of therapy, progression-free survival was not reached in the venetoclax group vs 14.0 months in the placebo group (HR = 0.54, 95% CI = 0.33–0.88).

A partial response or better was achieved in 82% of the venetoclax group vs 68% of the placebo group (P = .008), and a very good partial response or better was achieved in 59% vs 36% (P = .0003). A complete response was observed in 19% of the venetoclax group vs 3% of the placebo group (P = .0003), and a stringent complete response, in 8% vs 2% (P = .05). The median duration of response was not reached (95% CI = 21.0 months to not reached) with venetoclax vs 12.8 months with placebo (95% CI = 9.2–15.5 months).

Median overall survival was not reached in either group. At data cutoff for the first interim analysis, 52 overall survival events had occurred in the intention-to-treat population, including 41 (21%) in the venetoclax group and 11 (11%) in the control group (HR = 2.03, P = .034). The stopping boundary (P = .004) was not crossed. A second prespecified interim overall survival analysis is to be performed when approximately 87 events have occurred.

Adverse Events

Grade ≥ 3 adverse events occurred in 87% of the venetoclax group vs 87% of the control group. The most common in the venetoclax group were neutropenia (18% vs 7%), pneumonia (16% vs 9%), diarrhea (15% vs 11%), thrombocytopenia (15% vs 30%), and anemia (15% vs 15%). Serious adverse events occurred in 48% vs 50% of patients, with the most common in both groups being pneumonia (14% vs 13%); other serious adverse events included sepsis (3% vs 0%), orthostatic hypotension (3% vs 2%), and influenza (2% vs 4%). Overall rates of infection (80% vs 77%) and serious infection (28% vs 27%) were similar in the two groups. However, eight fatal infections (4%) occurred in the venetoclax group vs none in the control group.

Among the 40 deaths in the venetoclax group and 11 in the control group in the safety population, 13 (7%) vs 1 (1%) occurred within 30 days of the last dose of study drug and were considered treatment-emergent. Most treatment-emergent deaths occurred within 6 months of starting study treatment, including 10 in the venetoclax group and 1 in the control group. A total of 27 deaths (14%) vs 10 deaths (10%) occurred at > 30 days after the last dose of study treatment. Multiple myeloma was the most common cause of death during this period, accounting for 13 (7%) and 6 deaths (6%), respectively.

The investigators concluded: “The primary endpoint was met with a significant improvement in independent review committee-assessed progression-free survival with venetoclax vs placebo plus bortezomib and dexamethasone. However, increased mortality was seen in the venetoclax group, mostly because of an increased rate of infections, highlighting the importance of appropriate selection of patients for this treatment option.” The finding that patients with t(11;14) and those with high BCL2 expression appear to have a more favorable risk–benefit profile than patients without t(11;14) and with low BCL2 expression suggests that a biomarker-driven approach might be appropriate for the use of venetoclax in multiple myeloma. 

DISCLOSURE: The study was funded by AbbVie and Genentech. Dr. Kumar has served as a consultant or advisor to Cellectar; has served in an institutional consulting or advisory role for AbbVie, Amgen, Bluebird Bio, Celgene, GeneCentrix, Genentech/Roche, Janssen Oncology, Kite Pharma, Merck, Molecular Partners, Oncopeptides, and Takeda; has received institutional research funding from AbbVie, Carsgen Therapeutics Ltd., Celgene, Janssen Oncology, Kite Pharma, MedImmune, Merck, Novartis, Roche/Genentech, Sanofi, Takeda, and TeneoBio.

REFERENCE

1. Kumar SK, Harrison SJ, Cavo M, et al: Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (BELLINI). Lancet Oncol 21:1630-1642, 2020.