Venclexta-Darzalex Combos Show Strong Response Rates in Multiple Myeloma Trial, Early Data Show

Adding the antibody Darzalex (daratumumab) to Venclexta (venetoclax), a lymphoma and leukemia treatment, is a promising approach for multiple myeloma patients who failed prior treatment, particularly those with a common genetic abnormality called t(11;14), new Phase 1/2 data show.

The combination reduced tumor burden in nearly all — 92% — myeloma patients included in the trial. When Velcade (bortezomib) was added to the combination and given regardless of patients’ t(11;14) status, responses were also high (88%).

Despite the response rates, this and other Venclexta trials are now on partial hold due to safety concerns, namely that Venclexta may increase the risk of death in some myeloma patients.

An oral presentation with the findings, “First Analysis from a Phase 1/2 Study of Venetoclax in Combination with Daratumumab and Dexamethasone, +/- Bortezomib, in Patients with Relapsed/Refractory Multiple Myeloma” recently took place at the American Society of Hematology (ASH) 2019 Annual Meeting, held in Orlando, Florida, Dec. 7-10.

Venclexta, developed and marketed by Genentech and AbbVie, is a potent selective inhibitor of the B-cell lymphoma-2 (BCL-2) protein. It works by preventing cancer cells from over-producing this protein, priming them for programmed cell death.

The treatment is approved for certain lymphomas and leukemias, but clinical data suggests that Venclexta may also be beneficial for multiple myeloma patients who failed to respond to prior treatment regimens.

In particular, researchers have seen that Venclexta alone has encouraging efficacy in patients with the t(11;14) translocation, and that a combination of Venclexta and Velcade work well regardless of patients’ genetic characteristics.

Given the heterogeneity of myeloma, adding additional medications to these Venclexta regimens may improve their efficacy.

The ongoing M15-654 (NCT03314181) trial is designed to explore if the CD38 antibody Darzalex could increase the anti-tumor activity of the Venclexta single therapy and of Venclexta-Velcade in myeloma patients who had relapsed after or were refractory to prior treatments.

The study comprises two groups; group 1 has patients with the t(11;14) translocation who progressed after previous treatment with a proteasome inhibitor like Velcade and an immunomodulatory agent. Group 2 has patients who were given up to three prior lines of therapy, and are naive or sensitive to proteasome inhibitors. Patients in group 2 were enrolled regardless of their t(11;14) status.

The designation t(11;14) means there is a translocation, a chromosome segment that breaks off and changes position by attaching to another chromosome, namely from chromosome 11 to chromosome 14.

Patients in group 1 are being treated with a combination of Venclexta, Darzalex, and dexamethasone (a corticosteroid), while patients in group 2 are being given Velcade in addition to that triple combination regimen.

Both groups follow a two-stage design, in which patients first receive ascending doses of Venclexta to determine its optimal dose and regimen, after which an extension phase will continue to assess the safety and efficacy of the established dose.

At the time of data cut-off (May 2019), 48 patients had been enrolled in the trial, with 24 placed in group 1 and 24 in group 2. Group 1 had a median age of 63, and had been given a median of 2.5 prior therapies. All had been treated with a proteasome inhibitor and an immunomodulatory agent, and 42% had failed to respond to both these treatments.

After receiving the triple treatment in this trial, 92% of these patients showed a significant reduction in tumor burden.

In group 2, patients were a median age of 64, most had received one prior line of therapy, and six had the t(11;14) while the others did not. Most patients had failed to respond to a prior proteasome inhibitor and an immunomodulatory agent. Here, 88% responded to the four-therapy combination, including 58% with very good partial responses or better.

The most common adverse events in both groups were fatigue, diarrhea, nausea, insomnia, cough, headache, upper respiratory tract infection, constipation, an infusion related reaction, peripheral neuropathy, and indigestion. Eleven patients had a serious adverse event, five in group 1 and six in group 2.

Overall, this first analysis supports the benefits of Venclexta in combination with Darzalex and dexamethasone, with or without Velcade, “notably among t(11;14) patients treated with [Venclexta-Darzalex-dexamethasone] who had an [overall response rate] of 92%,” the researchers concluded.

The trial is scheduled to end in June 2024.