The BELLINI Trial
David Awad, PharmD
PGY2 Oncology Pharmacy Resident
Yale New Haven Hospital
New Haven, CT
Multiple myeloma (MM) is the second most common hematologic malignancy and is responsible for about 1% of all cancers and 10% of all hematologic malignancies.1-3 In this plasma cell dyscrasia, proliferation of cytogenetically defective malignant plasma cells leads to eventual end-organ dysfunction.4-6 Standard treatment of MM is comprised of different cocktails of agents with activity against plasma cells, including monoclonal antibodies, immunomodulatory drugs, proteasome inhibitors and corticosteroids.7
BELLINI Trial Attempts to Define the Role of Venetoclax in Patients with Relapsed or Refractory MM
The treatment landscape has evolved substantially over the past 15 years with the development of new, more effective targeted agents and regimens that possess a high level of anti-tumor activity.4,8 In spite of this progress, nearly all MM patients ultimately relapse, even those who experience a response to initial therapy, rendering the disease incurable at this point in time. 8-9
Venetoclax is a potent, small molecule inhibitor of the B-cell lymphoma-2 (BCL-2) protein. BCL-2 is an anti-apoptotic protein, which can be overexpressed in cancers, promoting cell survival.10-11 Inhibition of BCL-2 has shown significant activity in the treatment of acute myeloid leukemia, gaining venetoclax Food and Drug Administration (FDA) approval in 2018.12 BCL-2 overexpression is a potential driver of malignant proliferation and is a pathway for survival in MM cells.13 In vitro studies demonstrated the apoptotic activity of venetoclax in certain MM cells, particularly in those with t(11;14) translocation.14-15 The recently published BELLINI trial attempts to define the role of venetoclax in patients with relapsed or refractory MM.
The BELLINI trial was a randomized, double-blind, placebo-controlled, multicenter, Phase III trial that evaluated the efficacy and safety of venetoclax in combination with bortezomib and dexamethasone for the treatment of relapsed or refractory MM. Adult patients with MM who received one to three previous lines of therapy, had an Eastern Cooperative Oncology Group performance status of 2 or less, and were sensitive or naïve to proteasome inhibitors were included. Patients were excluded if they had previous treatment with BCL-2 inhibitors, allogeneic transplant within 16 weeks or autologous transplant within 12 weeks, grade 3 or worse peripheral neuropathy or grade 2 or worse peripheral neuropathy with pain. Patients were randomized 2:1 to receive venetoclax or placebo in combination with dexamethasone and bortezomib.
Venetoclax 800 mg was administered by mouth daily, bortezomib 1.3 mg/m2 subcutaneously or intravenously was administered days 1, 4, 8 and 11, and dexamethasone 20 mg was administered days 1, 2, 4, 5, 8, 9, 11 and 12 of a 21-day cycle for eight cycles. From cycle nine, venetoclax administration ceased, bortezomib was administered days 1, 8, 15 and 22 and dexamethasone was administered days 1, 2, 8, 9, 15, 16, 22 and 23 of a 35-day cycle. Venetoclax was dose reduced by 50% in patients receiving concomitant moderate CYP3A inhibitors, and by 75% in patients receiving strong CYP3A inhibitors. There was no venetoclax dose ramp-up per the protocol. All patients received herpes zoster prophylaxis.
The primary end point was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), duration of response, and rate of minimal residual disease negativity. Safety analysis was conducted in patients who received at least one dose of therapy.
Between July 19, 2016 and October 31, 2017, 291 patients were included in the study: 194 randomized to the venetoclax arm and 97 patients to the placebo arm. Fifty-four percent of the population had received at least two lines of prior therapy, 41% had previous exposure to proteasome inhibitors and immunomodulatory drugs and 60% had a previous stem cell transplant. High-risk disease was present in 17% of the population and 44% had International Staging System Stage I disease.
Median PFS was significantly longer in the venetoclax arm (22.4 months vs 11.5 months; HR 0.63 [95% CI 0.44-0.90] p=0.010). Median OS was not reached in either arm; however, there were twice as many deaths in the venetoclax arm than in the placebo arm (21.1% vs 11.3%; HR 2.03 [95% CI 1.04–3.94]). Duration of response was longer in the venetoclax arm (not reached vs 12.8 months) and ORR was significantly higher with venetoclax compared to placebo (82% vs 68%, p=0.0081). The proportion of patients who achieved a minimal residual disease negative response (10-5) was also significantly higher in the venetoclax arm than in the placebo arm (13% vs 1%, p=0.00066).
Of the total population, 35 patients were positive for t(11;14) translocations: 20 patients in the venetoclax arm and 15 patients in the placebo arm. Prespecified analysis showed that median PFS (not reached vs 9.5 months, p=0.004) was longer and ORR (90% vs 47%, p=0.0038) was higher in the venetoclax arm compared to placebo in patients with t(11;14) translocation. However, median OS was not significantly different (not reached in either group). A total of 177 patients had BCL-2 expression data, with high expression in 140 patients. Amongst those with high BCL2 expression, post-hoc analysis showed median PFS was significantly longer in the venetoclax arm compared to placebo (22.4 months vs 9.9 months). However, neither ORR (85% vs 75%) nor median OS (not reached in either group) were significantly different between arms.
In the safety analysis, 63% of patients in the venetoclax and 78% of patients in the placebo arm discontinued treatment. The most common grade 3 or higher treatment-emergent adverse events (TEAEs) were neutropenia (18% in the venetoclax arm vs 7% in the placebo arm), pneumonia (16% vs 9%), diarrhea (15% vs 11%), thrombocytopenia (15% vs 30%), and anemia (15% vs 15%). TEAEs led to dose reductions in 57 (30%) patients in the venetoclax arm and 15 (16%) patients in the placebo arm. Forty (21%) of 193 patients in the venetoclax arm and 11 (11%) of 96 patients in the placebo arm died. Of these deaths, 13 (7%) patients in the venetoclax arm and one (1%) patient in the placebo arm died within 30 days of the last dose of study drug and were considered treatment-emergent. Causes of death include disease progression (5% in the venetoclax arm vs 1% in the placebo arm), sepsis or septic shock (5% vs 1%), multiple myeloma (3% vs 3%) and cardiac arrest (2% vs none). In March 2019, the FDA placed a partial clinical hold of trials investigating venetoclax in multiple myeloma based on the interim analysis of the BELLINI trial.16 A protocol amendment to the BELLINI trial required patients receiving venetoclax to receive antimicrobial and Pneumocystis jiroveci pneumonia prophylaxis, in addition to influenza and pneumococcal vaccinations.
Previous Observations Confirmed; More Studies Underway
The BELLINI trial confirmed previous observations that the addition of venetoclax to bortezomib and dexamethasone provides a high overall response rate in certain patients with relapsed or refractory MM. Despite increases in response and PFS, the increased mortality rate raises questions regarding the safety of this combination.
The authors postulate this may be due to increased immunosuppressive effects of the regimen, leading to higher rates of infections. Longer PFS in patients with t(11;14) translocations or high BCL-2 expression demonstrate a potential role for venetoclax in the MM treatment algorithm. However, the lack of mortality difference observed may place this below the multiple alternative treatment regimens available in relapsed or refractory MM. While this regimen did not make its way into the NCCN guidelines, venetoclax and dexamethasone are listed as a treatment option for relapsed or refractory multiple myeloma in patients with t(11:14) translocation based on phase one data.17 Further studies are underway (NCT03314181, NCT03539744 and NCT02899052) to identify the true role of venetoclax in the treatment of MM.