Venetoclax for Myeloma: Details Emerge of Benefit, After Trial Stopped

Nancy A. Melville

June 24, 2019

UPDATED June 26, 2019 // AMSTERDAM — New data from the suspended clinical trial of venetoclax (AbbVie/Genentech) for the treatment of multiple myeloma (MM) show that some subsets of patients appeared to benefit from the therapy. The trial was put on hold because of safety concerns.

The phase 3 BELLINI trial was investigating the addition of venetoclax to the doublet of bortezomib (Velcade, Millennium) and dexamethasone (multiple brands) in the treatment of relapsed/refractory multiple myeloma (MM).

The new data from this trial "show that venetoclax is a useful drug in relapsed MM disease, albeit in a selected group of patients, and eventually this will be a biomarker-driven drug," coinvestigator Shaji Kumar, MD, of the Mayo Clinic, Rochester, Minnesota, told Medscape Medical News.

In presenting new data from the study here at the European Hematology Association (EHA) 2019 Annual Meeting, Kumar said that, consistent with findings from phase 1 and 2 trials, patients in the BELLINI study who appeared to show the most benefit and lowest risk were those with the translocation t(11;14) in myeloma cells.

"Patients with t(11:14) had consistent clinical benefit when treated with venetoclax plus bortezomib and dexamethasone, and the benefit-risk profile appears to be favorable in this MM subset," he said.

Earlier this year, the trial was put on partial hold after interim results showed nearly double the number of deaths among patients who received venetoclax compared to those who received bortezomib and dexamethasone without venetoclax, as reported by Medscape Medical News

The interim results from the trial showed that 41 deaths occurred among 194 patients in the venetoclax group (21.1%), compared to 11 deaths among 97 patients in the placebo arm (11.3%).

At the time, the US Food and Drug Administration (FDA) issued a partial hold on all ongoing clinical trials of venetoclax for the treatment of MM, an indication for which venetoclax has not been approved. Venetoclax, a highly selective oral inhibitor of BCL-2, is approved for use in the treatment for chronic lymphocytic lymphoma and acute myeloid leukemia.

On June 24, the FDA lifted a partial clinical hold on another trial in myeloma, the phase 3 CANOVA trial of veneotoclax in relapsed/refractory MM.

The CANOVA trial is evaluating venetoclax with dexamethasone vs pomalidomide (Pomalyst, Celgene) with dexamethasone in patients with relapsed/refractory MM that is positive for the translocation (t) abnormality.

"We are pleased to move forward with the CANOVA study which, with the t biomarker test, can help identify patients who may respond better to treatment and add clarity for physicians when choosing a therapy, if approved," Mohamed Zaki, MD, PhD, global head of hematology development at AbbVie, said in a statement. "We are working closely with regulatory authorities worldwide to continue our efforts to understand the potential of venetoclax for patients with multiple myeloma while continuing to advance research in patients with the t genetic abnormality."

Study Details

At the meeting, Kumar reported new clinical data from the BELLINI trial.

In that trial, 291 patients with relapsed/refractory MM were randomly allocated in a 2:1 ratio to receive either venetoclax or placebo in combination with bortezomib and dexamethasone. The overall response rates (ORRs) were 82% vs 68% (P < .01) in favor of the venetoclax-treated group.

The corresponding rates for very good partial response (VGPR) or better were 59% vs 36% (P < .01). The endpoint of rate of median progression-free survival (PFS) was met; that rate was superior and nearly doubled in the venetoclax group compared to the placebo group (22.4 months vs 11.5 months; hazard ratio [HR] = 0.630; P = .01).

Rates of minimum residual disease (MRD) negativity were also significantly higher in the venetoclax group, ranging from 7% to 19% in the venetoclax group to just 1% to 3% in the placebo group (P =.001).

In an analysis of key subgroups, margins between treatment groups were significantly wider for patients with the t(11;14) transcript; among those patients, responses were higher for patients who received venetoclax.

There were 35 patients with the t(11;14) transcript (12% of trial participants). In these patients, the ORRs were 90% vs 47% in favor of the venetoclax group (P = .004). The VGPR rates were 70% vs 27% (P = .016). The complete response (CR) rates were 45%, compared to just 7% in the placebo group (P = .017).

Rates of MRD negativity were strikingly higher in the venetoclax-treated patients with t(11;14), ranging from 20% to as high as 40%, compared to 0% in the placebo group (P = .006).

"We found high rates of complete responses and MRD negativity in the t(11;14) subgroup with venetoclax plus bortezomib and dexamethasone," Kumar said.

The median PFS rate in patients with t(11;14) in the venetoclax group was not reached; the median was 9.5 months in the placebo group (HR, 0.110; 95% confidence interval [CI], 0.022 – 0.560; P = .002).

"The progression-free survival benefit was most evident with venetoclax plus bortezomib and dexamethasone in the t(11;14) subgroup," Kumar said.

Importantly, although in the full study, the risk for death in the venetoclax group was doubled (HR, 2.027; 95% CI, 1.042 – 3.945), there was no significant difference in treatment groups among t(11;14) patients. The 18-month follow-up data that were presented showed one death in the venetoclax group and two in the placebo group (P = .36).

Higher-Risk Groups Also Identified

Conversely, subgroup analysis identified characteristics of patients who showed a higher risk for adverse events.

Kumar reported that "patients with ISS3, high-risk cytogenetics, and low BCL-2 expression were identified as subgroups associated with poor PFS outcomes when treated with venetoclax plus bortezomib and dexamethasone."

About a quarter of MM patients fit that high-risk profile. That was also the proportion of trial participants who had this profile, Kumar said.

Infections, Progressive Disease Leading Causes of Deaths

The primary causes of death in the full analysis of the BELLINI study were infections (7% with venetoclax vs 2% with placebo), progressive disease (9% vs 8%), or other causes (5% vs 1%). Treatment-emergent deaths typically occurred early in the course of treatment, within the first 6 months.

Among deaths occurring within 30 days of the last dose, eight occured within the venetoclax group, due to infection; none occurred in the placebo group. There were two deaths in the venetoclax group and one in the placebo group from progressive disease within 30 days.

Infection-related adverse events were similar between the groups, as were most other adverse events. In terms of common hemotologic adverse events, rates of thrombocytopenia were lower in the ventetoclax group (39% vs 52%), and rates of neutropenia were higher with venetoclax (32% vs 10%).

The findings suggest that "patients should be carefully followed for infections, and antibiotic prophylaxis would be recommended," Kumar said.

"Furthermore, until more data are available, a venetoclax and protease inhibitor combination should be avoided in patients with high-risk disease," he said.

"Intriguing and Thought Provoking"

In commenting on the research, Hari Parameswaran, MD, professor and chief of the Division of Hematology Oncology in the Department of Medicine at the Medical College of Wisconsin, in Milwaukee, said risks and benefits observed so far with the addition of venetoclax to treatment of MM give pause and that the new data are "intriguing and thought provoking."

"Generally in relapsed MM, we expect PFS and OS [overall survival] to track together," he explained to Medscape Medical News.

"Higher deaths immediately raise the possibility of higher treatment-emergent toxicity leading to death or shortened post-progression survival by some other biological mechanism.

"It is unclear if one or more of these mechanisms is at play here, since disease control was better in the venetoclax plus bortezomib and dexamethasone arm, but once progression happened, the survival time appeared to be shorter in the same arm.

"Another question is if this is dose-related and whether a lower dose of venetoclax or the addition of mandated infection prophylaxis would reduce mortality risk," he said.

Despite the evidence that the benefits appear to be superior in the t(11;14) population, Parameswaran said there are still concerns — even with those patients.

"Given the safety signal regarding OS, I would hesitate to say that this trial establishes the role of venetoclax plus bortezomib and dexamethasone, even in this population," he said.

"Clearly, longer-term follow-up and analysis of post-relapse survival are needed, even in this population," he said.

More data are needed to better understand the greatest risk — and who can benefit the most, Parameswaran said.

"We absolutely need to know the phenotype of patients that should avoid this drug, or if there is such a group at all," he said.

"On the other hand, given the promising results, especially in the t(11:14) subset, patients who are in a desperate clinical situation and have this mutation should consider cautious use of this combination in clinical trials or compassionate use protocols," he added.

Kumar has consultant/advisory roles with Takeda, Janssen Oncology, Amgen, AbbVie, Merck, Adaptive Biotechnologies, Celgene, Genentech/Roche, Oncopeptides, and Kite Pharma and receives research funding from Celgene, Takeda, AbbVie, Novartis, Sanofi, Janssen Oncology, Merck, Kite Pharma, MedImmune, and Genentech/Roche. Parameswaran has received grant support, consultancy fees, and honoraria from Takeda and AbbVie.

European Hematology Association (EHA) 2019 Annual Meeting: Abstract LB2601. Presented June 16, 2019.

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