Venetoclax-based regimen may extend survival in multiple myeloma

Venetoclax with bortezomib and dexamethasone demonstrated an acceptable safety profile and promising efficacy among patients with relapsed or refractory multiple myeloma, according to results of an open-label, phase 1b trial published in Blood.

B-cell lymphoma 2 (BCL-2) is the gene family that induces (proapoptotic) or inhibits (antiapoptotic) apoptosis. Overexpression of antiapoptotic proteins — including BCL-2, as well as myeloid cell leukemia sequence 1 (MCL-1) — is heterogeneous in myeloma cells.

“Overall, the clinical results seen with this combination are encouraging and support an ongoing phase 3 trial of this regimen,” Philippe Moreau, MD, head of the hematology department at University Hospital of Nantes in France, and colleagues wrote. “Agents that target these BCL-2 family members, including venetoclax and bortezomib, provide a novel therapeutic approach for multiple myeloma based on a strong mechanistic rationale.”

Agents with unique mechanisms of action may offer additional treatment options for patients with multiple myeloma who, despite medical advances, inevitably relapse or become refractory to therapy.

In preclinical studies, venetoclax (Venclexta; AbbVie, Genentech) — an orally bioavailable potent inhibitor of BCL-2 designed to restore the apoptotic pathway in malignant cells — enhanced activity of bortezomib (Velcade, Millennium/Takeda), a proteasome inhibitor that can inhibit MCL-1 indirectly, suggesting that co-targeting of BCL-2 and MCL-1 could be an effective treatment strategy in myeloma.

Researchers assessed the efficacy and safety profile of venetoclax in combination with bortezomib and dexamethasone.

The analysis included 66 patients (median age, 66 years; range, 38-79 years; stage II or III, 65%). Researchers assigned 54 patients to dose-escalation (50 mg to 1,200 mg once daily), and 12 patients to safety expansion (800 mg once daily) of oral venetoclax. All patients received 1.3 mg/m² subcutaneous bortezomib and 20 mg oral dexamethasone.

Safety and pharmacokinetics served as the primary study objectives. Secondary objectives included overall response rate, time to disease progression and, duration of response and biomarkers.

Patients had received a median of three prior therapies. More than one-third of patients (39%; n = 26) were refractory to prior bortezomib, 53% (n = 35) were refractory to lenalidomide and 59% (n = 39) had prior stem cell transplant.

Median time on study was 5.9 months for all patients, 2.9 months for those refractory to prior bortezomib and 9.1 months for nonrefractory patients.

Researchers reported an ORR of 67%, which included a 42% rate of very good partial response or better. Median duration of response was 9.7 months.

Among patients not refractory to bortezomib who had one to three prior therapies, researchers reported an ORR of 97% and very good partial response or better rate of 73%.

ORR appeared higher among patients with high vs. low BCL-2 expression (94% vs. 59%).

Median time to progression was 9.5 months.

“These response rates were observed despite most patients (39 of 66) receiving a dose of venetoclax that was inferior to 800 mg per day,” Moreau and colleagues wrote.

The combination of venetoclax, bortezomib and dexamethasone appeared generally well tolerated.

Common adverse events included diarrhea (46%), constipation (41%) and nausea (38%). The most common grade 3 or grade 4 events were thrombocytopenia (29%), anemia (15%) and neutropenia (14%).

Seventy percent of participants (n = 46) discontinued the study, mostly due to disease progression (n = 36) or adverse events (n = 5). Adverse events leading to discontinuation included respiratory and cardiac failure (n = 2), lung adenocarcinoma, Guillain-Barre syndrome and sepsis (n =1 for each).

Five deaths occurred during the study — four due to disease progression and one due to respiratory syncytial virus infection.

“Although no direct comparisons can be made between trials, the 94% response rate for patients who were bortezomib nonrefractory and who received one to three prior therapies appears to be encouraging based on recent studies combining bortezomib and dexamethasone with novel drugs such as panobinostat [Farydak, Novartis], daratumumab [Darzalex, Janssen], carfilzomib [Kyprolis, Amgen] and elotuzumab [Empliciti, Bristol-Myers Squibb],” Moreau and colleagues wrote. – by Chuck Gormley

Disclosures: AbbVie and Genentech funded this study. Moreau reports consultant roles with and honoraria from Amgen, Celgene, Janssen-Cilag, Novartis and Takeda. Please see the study for a list of all other authors’ relevant financial disclosures.