FDA Warning Issued for Investigational Venetoclax Use in Myeloma Trials


Be careful with the investigational use of venetoclax (Venclexta) for the treatment of patients with multiple myeloma, the FDA has warned in an alert to healthcare professionals and clinical investigators.

Be careful with the investigational use of venetoclax (Venclexta) for the treatment of patients with multiple myeloma, the FDA has warned in an alert to healthcare professionals and clinical investigators.

In the warning letter, the FDA reminded that the use of venetoclax in multiple myeloma is not currently an approved indication.

A recent review of interim data from the phase III BELLINI trial (NCT02755597) revealed an increase in the risk of death with the addition of the BCL-2 inhibitor compared to the control arm. Following this discovery, theFDA placed a partial clinical hold on all clinical trials of venetoclax in multiple myeloma. The hold, implemented on March 6, prevents the enrollment of new patients into such trials until the hold is lifted.

The BELLINI trial is exploring the combination of venetoclax with bortezomib (Velcade) and low-dose dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received 1 to 3 prior lines of therapy.

The FDA reviewed data of 291 patients from the BELLINI trial with a November 26, 2018 cutoff date for an interim analysis of overall survival. As of data cutoff, there were 41 deaths among 194 patients (21.1%) in the venetoclax arm and 11 deaths (11.3%) from the control arm, which included 97 patients. The hazard ratio was 2.03 (95% CI, 1.04-3.94), which amounted to about a 2-fold increase in the relative risk of death compared with the control regimen. Additionally, 6.7% of the patient deaths in the venetoclax arm were considered to be treatment emergent compared with 1.0% in the control arm.

Causes of death in the venetoclax arm beyond disease progression were attributed to infection, sepsis, pneumonia, and cardiac arrest.

Patients with multiple myeloma on trials of venetoclax who are experiencing a clinical benefit are able to continue on treatment once they reconsent, according to the FDA.

Already the trial has demonstrated an objective response rate of 82.0% (95% CI, 75.8%-87.1%) for patients receiving the venetoclax combination compared with 68.0% (95% CI, 57.8%-77.1%) for bortezomib and dexamethasone alone.

The primary endpoint of improved progression-free survival (PFS) had been met in the BELLINI trial after a median follow-up of 17.9 months. The median PFS was 22.4 months with added venetoclax compared with 11.5 months in the placebo arm (HR, 0.63; 95% CI, 0.44-0.90). The rate of minimal residual disease negativity was 13.4% (95% CI, 8.9%-19.0%) with the venetoclax regimen versus 1.0% (95% CI, 0%-5.6%) with the control regimen.

The rate of both severe, grade 3 to 5 adverse events (AEs) and serious AEs were similar between the 2 arms at 86.5% with venetoclax versus 87.5% with placebo and 48.2% versus 50.0%, respectively. In the venetoclax arm, the rate of infections was 79.8% and 77.1% of patients in the placebo arm also experienced infections. Serious infection-related AEs were observed in 28.0% of patients with the addition of venetoclax and 27.1% with bortezomib and dexamethasone alone.

Pneumonia was reported in 20.7% of patients receiving venetoclax and in 15.6% receiving the doublet with placebo. Serious pneumonia-related AEs were observed in 14.0% and 12.5% of patients receiving the venetoclax regimen and the control regimen, respectively.

The FDA stressed that the warning does not apply to existing approved indications for venetoclax, and patients already receiving the treatment for such indications should continue to take venetoclax as prescribed.


FDA Warns about the risks associated with the investigational use of Venclexta in Multiple Myeloma. FDA website. Published March 21, 2019. https://www.fda.gov/Drugs/DrugSafety/ucm634120.htm. Accessed March 22, 2019.

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