As reported in The Lancet Oncology by Shaji K. Kumar, MD, 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. The excess mortality reflected a higher incidence of fatalities related to infections.  

Shaji K. Kumar, MD

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). 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
• 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 was given on days 1, 2, 8, 9, 15, 16, 22, and 23 of 35-day cycles until disease progression or unacceptable toxicity.

Patients had received one to three prior therapies. The primary endpoint was progression-free survival as assessed by an independent review committee in the intention-to-treat population.

Progression-Free Survival and Other Efficacy Outcomes

At 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–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).

In stratification subgroups, median progression-free survival was 22.4 vs 12.6 months (HR = 0.75, 95% CI = 0.48–1.16) among those with prior proteasome inhibitor exposure and not reached vs 10.2 months (HR = 0.46, 95% CI = 0.24–0.88) among those who had not received prior proteasome inhibitor therapy. Median progression-free survival was 22.4 vs 11.4 months (HR = 0.75, 95% CI = 0.45–1.26) among those with one prior line of therapy and not reached vs 14.0 months (HR = 0.54, 95% CI = 0.33–0.88) among those with two or three prior lines of therapy. Among 74 vs 40 patients with t(11;14) (n = 20 vs 15) or high BCL2 gene expression (n = 66 vs 32) or both, median progression-free survival was not reached vs 9.9 months (HR = 0.21, P < .0001).

Partial response or better was achieved in 82% vs 68% of patients (P = .008), and very good partial response or better was achieved in 59% vs 36% (P = .0003). Complete response was observed in 19% vs 3% (P = .0003), and stringent complete response in 8% vs 2% (P = .05). Median duration of response was not reached (95% CI = 21.0 months–not reached) vs 12.8 months (95% CI = 9.2–15.5 months).

Median overall survival was not reached in either group. At data cutoff for 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%).

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. In total, 8 of the 13 deaths in the venetoclax group were associated with infection, including 5 patients (3%) who died from sepsis or septic shock with multiorgan dysfunction and 3 (2%) who died from pneumonia. Among 27 (14%) vs 10 deaths (10%) occurring at > 30 days after the last dose of study treatment, multiple myeloma was the most common cause, accounting for 13 (7%) and 6 deaths (6%), respectively. Overall, three deaths in the venetoclax group—including two from pneumonia and one from septic shock—were considered treatment-related; no deaths in the control group were considered treatment-related.

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.”

Dr. Kumar, of the Division of Hematology, Mayo Clinic, Rochester, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by AbbVie and Genentech. For full disclosures of the study authors, visit thelancet.com.