Venetoclax/Carfilzomib Combo Highly Effective for t(11;14) Myeloma

Luciano Costa, MD, PhD

The addition of venetoclax (Venclexta) to carfilzomib (Kyprolis) and dexamethasone (Kd) demonstrated a 100% objective response rate (ORR) with a very good partial response (VGPR) or better rate of 86% for patients with relapsed/refractory t(11;14) multiple myeloma, according to findings from an ongoing phase II study presented at the 2018 ASCO Annual Meeting.¹

Across the full population of evaluable patients treated at various dose levels (n = 30), the ORR was 83% for the combination, with a VGPR or better rate of 57%. In patients with high-risk cytogenetics (n = 8), the ORR was 88% for the combination of venetoclax and Kd, with a VGPR or better rate of 63%. In those with standard risk disease (n = 22), the ORR was 82% and the rate of VGPR or better was 55%.

"Venetoclax plus Kd has shown promising preliminary efficacy," said lead investigator Luciano J. Costa, MD, PhD, associate professor of Medicine Blood and Marrow Transplantation and Cell Therapy Program, University of Alabama at Birmingham. "Although responses are extremely high in the t{11;14), we also saw responses in patients at standard risk that were comparable to those with high-risk cytogenetic abnormalities."

The ongoing phase II study enrolled 42 patients across cohorts exploring various doses of the venetoclax and carfilzomib. Dexamethasone was given at a consistent 40 mg dose. In cohort 1 and 2, patients received carfilzomib at 27 mg/m² on days 1, 2, 8, 9, 15, and 16 with dexamethasone on day 1, 8, 15, and 22. Venetoclax was prescribed at 400 mg/day and in cohort 1 and at 800 mg/day in cohort 2. In cohort 3, patients received venetoclax at 800 mg/day with carfilzomib at 70 mg/m² and dexamethasone weekly. A maximum tolerated dose was not reached, with cohort 3 being explored further in an expansion cohort.

In all efficacy evaluable patients, 7% of patients had a stringent complete response (sCR) and 17% had a CR. In those with t(11;14) myeloma, responses consisted of a sCR for 14% of patients and a CR for 29%. Those with high-risk cytogenetics had a CR rate of 25% and there were no sCRs.

In those refractory to a PI (n = 14), the ORR was 86% and the rate of VGPR or better was 79%. Seven percent of patients had an sCR and 14% had a CR. In those refractory to an IMiD (n = 19), the rate of VGPR or better was 53% and the ORR was 79%. The rate of CR and sCR was 5% each. In double refractory patients (n = 10), the ORR was 80% and the VGPR or better rates were 80%, with sCR and CR in 10% of patients each.

When examining the response rates, Costa noted that when a higher dose of each treatment was given it resulted in better outcomes. "These efficacy results contain all of the patients from the lower doses and the higher doses. That might be bringing down the median results," he said.

The cohort 3 dose of venetoclax at 800 mg and carfilzomib at 70 mg/m² is being explored in an expansion cohort, with 14 patients already enrolled. This dose was also determined based on findings from the CHAMPION-1 trial, wherein carfilzomib showed promise at 70 mg/m² in a once-weekly schedule.²

At the April data cutoff, the median time on therapy was 5.3 months in those evaluable for efficacy. One patient discontinued treatment due to an acute myocardial infarction and unstable angina. There were 3 deaths across all patients in the trial from respiratory arrest, pneumonia, and an unexplained cause that was potentially connected to carfilzomib.

Across all patients enrolled, grade 3/4 adverse events (AEs) occurred in 69% of patients, and most frequently consisted of lymphocyte count decrease (24%), white blood cell count decrease (10%), hypertension (7%), fatigue (7%), and platelet count decrease (7%). Serious AEs occurred in 29% of patients.

One patient experienced tumor lysis syndrome (TLS). This patient had t(11;14) disease with >80% bone marrow infiltration at screening. Following hospitalization and treatment with hydration and allopurinol, the TLS resolved and treatment was resumed.

"To date, the combination of venetoclax/Kd appears tolerable with no additional safety concerns compared with what is seen with standard high-dose carfilzomib," Costa said.

Promising efficacy has previously been demonstrated with single-agent venetoclax in patients with multiple myeloma, specifically those with t(11;14) alterations. In a phase I study,³ the ORR was 40% and the rate of VGPR or better was 27% with single-agent venetoclax in 30 patients with relapsed/refractory t(11;14) multiple myeloma.

In combinations, a phase Ib study showed promise for the addition of venetoclax to bortezomib (Velcade) and dexamethasone for patients with relapse/refractory multiple myeloma.⁴ The ORR in this study was 68% and the rate of VGPR or better was 40%. In those with the t(11;14) alteration, the ORR was 78%. In this study, responses were highest in patients with BCL2 expression. In this group, the ORR was 94% and the rate of VGPR or better was 66%.

Findings for BCL2 were not yet available for the phase II trial exploring venetoclax plus Kd. However, Costa noted that "Venetoclax exposures when co-administered with carfilzomib appear comparable to those observed when venetoclax was co-administered with bortezomib.”

References:

1. Costa LJ, Stadtmauer EA, Morgan GJ, et al. Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma. J Clin Oncol. 2018; 36 (suppl; abstr 8004).
2. Berenson JR, Cartmell A, Bussudo A, et al. CHAMPION-1: a phase 1/2 study of weekly carfilzomib and dexamethasone for relapsed or relapsed and refractory multiple myeloma. Blood. 2016;127(26):3360-3368.
3. Kumar S, Kaufman JL, Gasparetto C, et al. Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood. 2017;130:2401-2409.
4. Moreau P, Chanan-Khan A, Roberts AW, et al. Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM. Blood. 2017;130:2392-2400.

A phase III study is currently examining the addition of venetoclax to bortezomib and dexamethasone for patients with multiple myeloma, regardless of t(11;14) status. The study has enrolled 291 patients, with a primary endpoint of PFS. A secondary outcome measure is focused on PFS in patients with BCL2 expression. The primary completion date for the study is September 2019 (NCT02755597).

<<< 2018 ASCO Annual Meeting

Of the 42 enrolled patients, 30 were evaluable for efficacy. The median age across all patients was 67 years (range, 37-79), and patients had stage I (37%) or II and III disease (63%). In the efficacy evaluable group, 23% had t(11;14) myeloma and 27% were deemed to have high-risk cytogenetics. The median number of prior therapies was 2, with 47% refractory to a prior proteasome inhibitor (PI) and 62% refractory to an immunomodulatory drug (IMiD). A third of patients were refractory to both an IMiD and PI.