In the global randomized phase III CANOVA study, venetoclax plus dexamethasone (VenDex) demonstrated numerically longer progression-free survival compared with pomalidomide and dexamethasone (PomDex) in patients with t(11;14)-positive relapsed or refractory multiple myeloma, though the difference was not statistically significant. In a post hoc sensitivity analysis, however, median progression-free survival was significantly improved (more than doubled), and benefits were observed in other efficacy measures, according to Maria-Victoria Mateos, MD, PhD, Consultant Physician in the Hematology Department and Associate Professor of Medicine at the University of Salamanca, Spain, who reported the findings at the International Myeloma Society (IMS) 2023 Annual Meeting.¹

Maria-Victoria Mateos, MD, PhD

As Dr. Mateos pointed out, cytogenetic abnormalities impact outcomes in myeloma, but biomarker-directed therapies are lacking in this setting. The t(11;14) alteration is the most common translocation in myeloma, and in disease harboring t(11;14), the antiapoptotic protein BCL2 promotes cell survival. Venetoclax is a highly selective, potent BCL2 inhibitor that has shown encouraging efficacy in patients with t(11;14)-positive relapsed or refractory myeloma.²

Also presented at the IMS meeting was a phase II study exploring the benefit of combining venetoclax with carfilzomib/dexamethasone, based on previous findings that proteasome inhibitors and corticosteroids may enhance BCL2 dependency. The results of the first randomized efficacy data for this regimen in t(11;14)-positive patients—demonstrating high response rates—were presented by Jonathan Kaufman, MD, Professor of Hematology and Oncology at Emory University School of Medicine, Atlanta.³

“Having looked at all the data presented here, it is very clear to me that two things are true: one, venetoclax is effective in patients with t(11;14)-positive myeloma, and two, there is toxicity, as there is with every drug we use. I think it is our duty, our responsibility as myeloma investigators [along with] our pharmaceutical partners and the regulatory agency, to make this medication available to our patients,” Dr. Kaufman commented during the discussion of the CANOVA trial.

About CANOVA

Dr. Mateos presented the primary analysis of CANOVA, which evaluated VenDex vs PomDex in 263 patients with t(11;14)-positive relapsed or refractory myeloma. Patients had received at least two prior lines of therapy, had prior exposure to a proteasome inhibitor, and had relapsed on or were refractory to lenalidomide.

Patients were randomly assigned to receive venetoclax at 800 mg daily or pomalidomide at 4 mg daily on days 1 to 21 of a 28-day cycle, both with dexamethasone at 40 mg weekly. The primary endpoint was progression-free survival per independent review in the intent-to-treat population.

“[I]t is very clear to me that two things are true: one, venetoclax is effective in patients with t(11;14)-positive myeloma, and two, there is toxicity, as there is with every drug we use.”

— Jonathan Kaufman, MD

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Approximately one-third of both arms were triple-class–refractory. Patients allocated to VenDex tended to be more heavily pretreated, but otherwise baseline characteristics were similar. As of data cutoff, 28 patients remained on VenDex and 13 remained on PomDex. Among 102 patients discontinuing VenDex, 83 did so because of disease progression. Of 114 patients stopping PomDex, 73 had progressive disease.

Progression-Free Survival Benefit: Two Analyses

At a median follow-up of approximately 2 years, the primary endpoint of progression-free survival was numerically longer with VenDex than PomDex; however, the difference did not meet statistical significance. Median progression-free survival was 9.9 months with VenDex and 5.8 months with PomDex (hazard ratio [HR] = 0.823; P = .237), Dr. Mateos reported.

To try to clarify this potential clinical benefit, investigators performed a post hoc sensitivity analysis. As Dr. Mateos explained, 21 patients allocated to PomDex vs 4 receiving VenDex discontinued treatment for reasons other than progressive disease or adverse events (ie, “physician decision, withdrawal by patient, or other”). “In addition,” she said, “we realized some patients initiated subsequent antimyeloma therapy without meeting the stringent International Myeloma Working Group criteria for disease progression, and these patients were censored in the primary progression-free survival analysis. So, we conducted a post hoc sensitivity analysis in which the events were disease progression according to the independent review committee’s data but also the initiation of a new line of therapy.”

This post hoc analysis found median progression-free survival to be significantly longer—more than doubled—with VenDex: 9.4 months vs 4.0 months (HR = 0.651; P = .0003). Additionally, the time to next treatment was longer with VenDex at 21.2 months vs 8.3 months (HR = 0.546; P = .001). VenDex also resulted in higher response rates (62% vs 34%; P < .001) and deeper responses (very good partial responses or better in 39% vs 14%). None of the PomDex arm achieved measurable residual disease (MRD) negativity, but with VenDex, MRD negativity rate was 8% when analyzed at a sensitivity threshold of 10^–5 and 6% at 10^–6.

At a median follow-up of about 25 months, VenDex resulted in numerically longer overall survival than PomDex: a median of 32.4 months vs 24.5 months (HR = 0.697; P = .067). There were 62 patients (47%) in the VenDex arm and 78 patients (60%) in the PomDex arm who received subsequent antimyeloma therapy, with types of treatments generally balanced between the arms, she said.

Safety Profile

Although the median duration of treatment exposure was 9.1 months with VenDex vs 4.3 months with PomDex, grade 3 or 4 events were more common with PomDex: 83% vs 67% with VenDex, with 61% and 43%, respectively, related to the study drug. However, more treatment-related adverse events led to death with VenDex: 8% (n = 11) vs 3% (n = 4). For seven of these patients treated with VenDex, the deaths were from pneumonia, with no particular trend observed for the timing of infections or deaths, pathogen type, or disease status. Although patients at high risk for infection could receive immunoglobulin replacement therapy, none of these patients did, she said.

Venetoclax in Combination

In the open-label multicenter phase II study presented by Dr. Kaufman, 58 patients (50 in the randomized part of the study) with t(11;14)-positive relapsed or refractory myeloma received venetoclax at 400 mg or 800 mg, plus weekly carfilzomib at 70 mg/m² and dexamethasone at 40 mg (VenKd), or carfilzomib/dexamethasone (Kd) alone. Median follow-up for progression-free survival was 23 months with VenKd and 17 months with Kd.

“From an efficacy standpoint, you see clear differences in the combined venetoclax arms [both doses] vs carfilzomib/dexamethasone,” he said. The overall response rate was 63% with Kd, increasing to 92% with the addition of venetoclax. Rates of very good partial response or better were 42% and 82%, respectively. Response rates by venetoclax dose were 89% with 400 mg and 95% with 800 mg.

“Of note, improvement in response rates translated into what appears to be an improvement in progression-free survival,” Dr. Kaufman noted. Median progression-free survival by investigator assessment was 32.3 months with VenKd vs 14.2 months with Kd, with median duration of response of 41.5 months vs 16.3 months, respectively. By venetoclax dose, median progression-free survival was 42.4 months with 800 mg and 32.2 months with 400 mg.

“The efficacy observed among daratumumab- and lenalidomide-refractory patients, as well as those with gain(1q) and/or del(17p), who were treated with venetoclax plus Kd was encouraging, with response rates ranging from 90% to 96%,” Dr. Kaufman added. Median overall survival was not reached in either group.

The safety profile of the combination was consistent with the known safety profiles of each agent, and no new safety signals emerged. “With that said, we do see increased toxicity, both hematologic and nonhematologic, with the three-drug regimen vs two, but it’s a level of toxicity we would expect for the individual medications,” he commented, noting treatment exposure was also much longer with VenKd. As expected, there were more infections with VenKd, with those of any grade occurring in 85% with 800 mg and 68% with 400 mg vs 33% with Kd alone.

More mature data and a larger sample size are needed to determine the optimal venetoclax dose, Dr. Kaufman said. At this point, there are no clear differences between the 400-mg dose and the 800-mg dose, which both appear superior to Kd alone. Enrollment in the study is ongoing. 

DISCLOSURE: Dr. Mateos has received honoraria from or served on advisory boards of Janssen, Celgene, Amgen, Takeda, AbbVie, GlaxoSmithKline, Oncopeptides, Sanofi, Pfizer, Roche, and Stemline. Dr. Kaufman has served as a consultant for AbbVie, Sanofi, Bristol Myers Squibb, and Incyte.

REFERENCES

1. Mateos MV, Beksac M, Dimopoulos MA, et al: Results from the randomized, open-label phase 3 CANOVA study of venetoclax-dexamethasone versus pomalidomide-dexamethasone in patients with t(11:14)-positive relapsed/refractory multiple myeloma. International Myeloma Society 2023 Annual Meeting. Abstract OA-52. Presented September 29, 2023.

2. Kaufman JL, Gasparetto C, Schjesvold FH, et al: Targeting BCL-2 with venetoclax and dexamethasone in patients with relapsed/refractory t(11;14) multiple myeloma. Am J Hematol 96:418-427, 2021.

3. Kaufman JL, Gasparetto C, Kovacsovics T, et al: First results from the randomized portion of a phase 2 study of venetoclax plus carfilzomib-dexamethasone vs carfilzomib-dexamethasone in patients with t(11;14)-positive relapsed/refractory multiple myeloma. International Myeloma Society 2023 Annual Meeting. Abstract OA-29. Presented September 28, 2023.