The phase 3 trial found that this treatment improves progression-free survival (PFS) during 18.7 months of follow-up, although patients treated with Venclexta (venetoclax) a had increased mortality rates compared with those treated with placebo.
Treatment with Venclexta (venetoclax), in addition to Velcade (bortezomib) and dexamethasone, significantly improved progression-free survival (PFS) in patients with relapsed or refractory multiple myeloma (MM) compared with placebo, according to results of the BELLINI trial published in The Lancet Oncology.
Despite this significant improvement, researchers observed an higher mortality rate in patients treated with Venclexta compared with placebo, which may be due to an increased rate of infections.
“Multiple myeloma remains an incurable malignancy despite new therapies that have become available,” said Dr. Shaji Kumar, Mark and Judy Mullins Professor of Hematological Malignancies, consultant in the division of hematology and professor of medicine at Mayo Clinic, in an interview with CURE®.
“Given this, newer therapies that work through different mechanisms can make a significant impact on the outcomes of patients with this cancer. From that standpoint, venetoclax offers a new therapeutic approach for these patients.”
Kumar added that findings from this trial may also lead to new types of therapies and limiting them to patients with the most benefit. “The fact that we observed the activity primarily in the context of translocation t(11;14) (a genetic abnormality) also opens up the opportunity to develop a biomarker-guided therapy for this cancer,” said Kumar. “The increased risk of death observed in patients who did not have this translocation also enables us to limit the therapy to those patients who (have) the maximum benefit.”
Venclexta is an oral BCL-2 inhibitor that induces apoptosis, or programmed cell death, the study authors wrote. Results from a phase 1 trial previously showed that Venclexta with Velcade and dexamethasone was safe and tolerated in patients with relapsed or refractory MM.
In this current phase 3 trial, researchers assessed the efficacy and safety of this treatment in 291 patients (median age, 66 years; median time from diagnosis, 3.5 years) with relapsed or refractory MM. These patients previously received one to three lines of therapy and were either naïve or sensitive to proteasome inhibitors (ie, Velcade). In addition, patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, which indicates that a patient can at least walk and perform selfcare tasks, although work activities may be limited.
Patients were randomly assigned 800 mg of Venclexta orally once per day (194 patients; median age, 66 years; 50% men) or placebo (97 patients; median age, 65 years; 57% men). Both groups also received 1.3 mg/m2 of Velcade subcutaneously or intravenously and 20 mg of dexamethasone orally. The first eight cycles of the assigned treatment were given in 21-day cycles, which increased to 35-day cycles from the ninth cycle until unacceptable toxicity, disease progression or when a patient withdrew from the trial.
The primary endpoint for this trial was PFS based on assessment by an independent review committee, or a team not associated with the trial to potentially minimize bias. Study authors defined PFS as the time from randomization (when patients received their treatment assignment) to the first instance of disease progression or all-cause death. Researchers also analyzed safety in patients who received at least one dose of a drug assessed in this trial. Follow-up was conducted for a median of 18.7 months.
Disease progression or death occurred in 39% of patients in the Venclexta group vs. 56% of those in the placebo group during follow-up. The median PFS for patients assigned Venclexta was 22.4 months compared with 11.5 months in those assigned placebo.
The most common treatment-related adverse events, including severe events, observed in the Venclexta and placebo groups included pneumonia (16% vs. 9%, respectively); neutropenia, or a low number of white blood cells called neutrophils (18% vs. 7%, respectively); anemia, or a lack of healthy red blood cells (15% for both groups); thrombocytopenia, or a low level of platelets called thrombocytes (15% vs. 30%, respectively) and diarrhea (15% vs. 11%, respectively).
Serious adverse events related to the treatment occurred in 48% of patients assigned Venclexta compared with 50% of those assigned placebo. This included 4% of patients in the Venclexta group with fatal infections compared with no fatal infections in the placebo group.
Three deaths in patients assigned Venclexta were related to the treatment, with two deaths related to pneumonia and one related to septic shock, or an infection that leads to dangerously low blood pressure levels and organ failure. In contrast, no deaths in patients assigned placebo were related to the treatment.
“Ongoing clinical trials are examining venetoclax and combination of this drug with other standard of care myeloma therapies in patients with translocation t(11;14),” said Kumar. “A better assessment of the efficacy and toxicity of this drug, especially when used in different combinations, will be critical to guide us in terms of its use in this patient population. We also need to understand the mechanisms of resistance that have been observed in other patients and in patients who initially responded, but subsequently had disease progression. These biological studies, in turn, will allow us to develop rational combinations in order to extend the benefits from this drug.”
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