Venetoclax Plus Dexamethasone Misses PFS End Point in t(11;14)+ R/R Multiple Myeloma

Mariana Cota Stirner, MD, PhD

The combination of venetoclax (Venclexta) and dexamethasone (VenDex) failed to significantly improve progression-free survival (PFS) over pomalidomide (Pomalyst) plus dexamethasone (PomDex) in patients with t(11;14)-positive, relapsed or refractory multiple myeloma who have previously received at least 2 therapies, missing the primary end point of the phase 3 CANOVA trial (NCT03539744).¹

The median PFS with VenDex was 9.9 months vs 5.8 months with PomDex (HR, 0.823; 95% CI, 0.596-1.136; P = .0237). Moreover, VenDex elicited an overall response rate (ORR) of 62% vs 35% with PomDex (P < .001), with very good partial response (VGPR) or better rates of 39% vs 14%, respectively (P < .001). The median overall survival (OS) with PomDex was 32.4 months vs 24.5 months with PomDex (HR, 0.697; 95% CI, 0.472-1.029; P = .067).

Data from additional prespecified analyses showed that the investigator-assessed PFS with VenDex was 9.1 months vs 4.9 months with PomDex (HR, 0.737; 95% CI, 0.543-1.000; P = .050). The median time to next treatment was extended with VenDex vs PomDex at 21.2 months and 8.3 months, respectively (HR, 0.546; 95% CI, 0.385-0.776; P = .001).

The toxicity profile of VenDex was found to be generally consistent with what has been shown with both agents alone, with new no signals observed. The most common adverse effects (AEs) reported in more than 20% of patients included infection (61%), diarrhea (41%), lymphopenia (24%), and nausea (22%). With PomDex, the most common AEs were neutropenia (63%), infection (57%), thrombocytopenia (39%), and anemia (35%).

“While the CANOVA trial did not meet its primary end point, given the potential favorable trends seen in the study, we will discuss these data with health authorities in the near future,” Mariana Cota Stirner, MD, PhD, therapeutic area head oncology hematology at AbbVie, stated in a press release. “We remain committed to elevating the standard of care for [patients with] blood cancer around the world, including patients with multiple myeloma.”

The open-label, multicenter, randomized phase 3 CANOVA study enrolled patients (n = 263) with a documented diagnosis of multiple myeloma and t(11;14) positivity based on International Myeloma Working Group criteria who were at least 18 years of age and who had previously received 2 or more therapies.²

Patients needed to have measurable disease at the time of screening, have documented disease progression on or within 60 days following the completion of their last therapy, and have received at least 2 consecutive cycles of a proteasome inhibitor and lenalidomide (Revlimid) and be relapsed or refractory to that agent. They also were required to have an ECOG performance status of 0 to 2.

They could not have previously received venetoclax, another BCL-2 inhibitor, or pomalidomide, nor could they have a history of other active malignancies within the past 3 years before the trial. Other exclusion criteria included having evidence of ongoing graft-vs-host disease, known central nervous system involvement, or previous treatment with allogeneic or syngeneic stem cell transplant (SCT) within 16 weeks before randomization or autologous SCT within 12 weeks before randomization.

Study participants were randomly assigned 1:1 to receive oral venetoclax at a once-daily dose of 800 mg or oral pomalidomide at a once-daily dose of 4 mg on days 1 to 21 of 28-day cycles.³ Patients in both arms received dexamethasone at a once-weekly dose of 40 mg; in those aged 75 years or older, the drug was given at a dose of 20 mg. Treatment continued until progressive disease, intolerable toxicity, or study withdrawal.

Key stratification factors included age at randomization (<65 years vs ≥65 years), prior lines of therapy (2 vs 3 vs ≥4), and International Staging System stage at screening (I vs II vs III).

In addition to independent review committee–assessed PFS serving as the trial’s primary end point, secondary end points included ORR, duration of response, time to response and progression, minimal residual disease negativity rate defined at 10^-5 threshold, safety, patient-reported outcomes, and pharmacokinetics.

In March 2019, the FDA placed a partial clinical hold on all clinical trials examining venetoclax for use as a multiple myeloma treatment.⁴ The hold followed a review of findings from the phase 3 BELLINI trial (NCT02755597), in which a higher proportion of deaths was observed in the venetoclax arm vs the control arm, at 21% vs 11%, respectively (HR, 2.027; 95% CI, 1.042-3.945).⁵

The partial hold was lifted after an agreement was reached regarding revisions to the CANOVA study protocol, which included new risk mitigation measures, protocol-specified guidelines, and fully updated criteria.⁶

References

1. AbbVie presents results from phase 3 CANOVA study of venetoclax in patients with relapsed or refractory multiple myeloma. News release. AbbVie. September 29, 2023. Accessed October 6, 2023. https://news.abbvie.com/news/press-releases/abbvie-presents-results-from-phase-3-canova-study-venetoclax-in-patients-with-relapsed-or-refractory-multiple-myeloma.htm
2. A study designed to evaluate the safety and efficacy of venetoclax plus dexamethasone (VenDex) compared with pomalidomide plus dexamethasone (PomDex) in participants with t(11;14)-positive relapsed or refractory multiple myeloma. ClinicalTrials.gov. Updated October 2, 2023. Accessed October 6, 2023. https://clinicaltrials.gov/study/NCT03539744
3. Mateos M, Moreau P, Dimopoulos M-A, et al. A phase 3, randomized, multicenter, open-label study of venetoclax or pomalidomide in combination with dexamethasone in patients with t(11;14)-positive relapsed/refractory multiple myeloma. Presented at: 2020 ASH Annual Meeting; December 5-8, 2020; San Diego, CA. Abstract 2319. https://ash.confex.com/ash/2020/webprogram/Paper136192.html
4. AbbVie provides update on Venclexta/Venclyxto (venetoclax) multiple myeloma program. News release. AbbVie. March 29, 2019. Accessed October 6, 2023. https://news.abbvie.com/news/abbvie-provides-update-on-venclextavenclyxto-venetoclax-multiple-myeloma-program.htm
5. Kumar S, Harrison S, Cavo M, et al. A phase 3 study of venetoclax or placebo in combination with in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma. Presented at: 2019 European Hematology Association Congress; June 13-16, 2019; Amsterdam, The Netherlands. Abstract LB2601.
6. AbbVie announces US FDA lifts partial clinical hold on phase 3 study of venetoclax in patients with multiple myeloma positive for the t(11;14) genetic abnormality. News release. AbbVie. June 24, 2019. Accessed October 6, 2023. https://news.abbvie.com/news/press-releases/abbvie-announces-us-fda-lifts-partial-clinical-hold-on-phase-3-study-venetoclax-in-patients-with-multiple-myeloma-positive-for-t1114-genetic-abnormality.htm