Venetoclax with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma

Venetoclax, an oral B-cell lymphoma 2 (BCL-2) inhibitor, has been studied in combination with other agents in the treatment of multiple myeloma (MM), particularly in the setting of relapsed or refractory (RR) disease. The latest results from the BELLINI trial (NCT02755597) investigating venetoclax combined with the proteasome inhibitor bortezomib and dexamethasone demonstrated significantly higher median progression-free survival compared with the control arm; click here for the visual abstract summarizing data presented at 63rd American Society of Hematology Annual Meeting and Exposition.

Carfilzomib, a new proteasome inhibitor, causes apoptosis of MM cells, and indirectly promotes BCL-2 dependency in MM cells.¹ Given the previous success of venetoclax in combination with other agents that increase BCL-2 dependency, Luciano Costa and colleagues published the results of their phase II open-label dose-escalation trail  (NCT02899052) of venetoclax plus carfilzomib and dexamethasone (VenKd) in patients with RRMM in Blood Advances.¹ The study is summarized in this article.

Study design

• Patients received treatment with VenKd at one of four dose-finding levels or as part of the expansion cohort (Figure 1) until disease progression or intolerable adverse events (AEs).
• Of note, following the results of the BELLINI study in which higher rates of infection and infection-related death were observed in the venetoclax plus bortezomib/dexamethasone arm, antibiotic prophylaxis was implemented in this study.

Figure 1. Treatment regimens*^†

d, dexamethasone; IV, intravenous; K, carfilzomib; PO, oral; Ven, venetoclax.
*Adapted from Costa et al.^1
†PO and IV fluids were given ≥72 hours prior to the first dose of venetoclax and carfilzomib. Prophylactic antibiotics and antivirals were also given.
^‡Carfilzomib was administered at 20 mg/m² during the first week and was increased to the target dose in Cycle 1 on Day 8.

Baseline characteristics

Patients ≥18 years of age with RRMM were eligible for the study, with inclusion criteria including 1–3 prior lines of therapy, an Eastern Cooperative Oncology Group performance status ≤2, and measurable disease. Patients who had received carfilzomib previously and those with disease refractory to any BCL-2 inhibitor, significant cardiovascular disease, or Grade ≥3 peripheral neuropathy were excluded. Baseline characteristics are shown in Table 1.

Table 1. Baseline characteristics*

Results

Overall, 20 patients were recruited to the four dose-finding cohorts and a further 29 were included in the expansion cohort. Most patients received 70 mg/m² carfilzomib (71%) and 800 mg venetoclax (92%). The maximum tolerated dose was not reached.

Safety

• No patients in the dose-finding cohorts experienced a dose-limiting toxicity.
• All patients experienced ≥1 treatment-emergent adverse event (TEAE), and 92% of patients experienced Grade 3 or 4 TEAEs. The most common any grade and Grade ≥3 TEAEs are shown in Table 3.
• Serious TEAEs (defined as AEs that were life threatening, required medical intervention to prevent serious outcome, or resulted in significant disability or death) occurred in 53%, which included pneumonia (14%), influenza (6%), acute kidney injury (4%), congestive cardiac failure (4%), and hypoxia (4%).
• Rates of infection were similar to those observed with venetoclax monotherapy.
• Five deaths occurred, including in two patients due to Grade 5 infections (non-treatment-emergent pulmonary aspergillosis and treatment-emergent influenza B), one patient due to respiratory arrest, one due to an unexplained cause possibly related to carfilzomib, and one due to non-treatment-emergent disease progression.

Table 3. A summary of the most common TEAEs in all patients*

Efficacy

Response rates and minimal residual disease negativity in all patients, as well as according to important patient subgroups, are shown in Figure 2 and Table 4.

Figure 2. ORR and best overall response in all patients and key subgroups*

Best overall responses and overall response rates in all patients and depending on A t(11;14) status, BCL-2 gene expression, and B prior therapy.
BCL2, B-cell lymphoma 2; BOR, best overall response; CR, complete response; IMiD, immunomodulatory drug; ORR, overall response rate; PI, proteasome inhibitor; PR, partial response; sCR, stringent CR; SD, stable disease; VGPR, very good partial response.
*Data from Costa et al.¹

Table 4. MRD negativity, DOR, and PFS in all patients and key subgroups*

Conclusion

The novel combination of VenKd in patients with RRMM demonstrated promising, durable responses, with generally superior outcomes observed in patients with t(11;14) and high BCL-2 gene expression.

The safety profile was similar to that observed in trials with carfilzomib monotherapy and carfilzomib combination therapy with dexamethasone, as well as triplet therapy with the further addition of daratumumab. Rates of cytopenia were slightly higher in this study compared with other combination studies of carfilzomib, likely due to the venetoclax AE profile. This aside, it appears the addition of venetoclax to carfilzomib and dexamethasone did not increase treatment toxicity.

This study further supports a biomarker-driven approach for venetoclax treatment in MM; however, given the limited sample size and lack of randomization, further investigation with prospective clinical studies of VenKd is warranted.