SAN DIEGO—Venetoclax, the oral BCL-2 inhibitor approved by the US Food and Drug Administration to treat chronic lymphocytic leukemia (CLL) patients with 17p deletion, is also showing activity in multiple myeloma (MM) patients, particularly those with t(11;14).
Final results of a phase 1 study showed venetoclax to be safe as monotherapy in relapsed or refractory MM, producing a response rate of 40% in patients with the translocation and 21% overall.
Preliminary results of the study were presented at the 2015 ASH Annual Meeting, and final results were presented at the 2016 ASH Annual Meeting.
“So I think we have a drug that potentially can change the outcome of a lot of patients with myeloma,” Shaji Kumar, MD, of the Mayo Clinic in Rochester, Minnesota, said during the presentation of the findings at ASH (abstract 488*).
“[It] also opens the possibility of being combined with a variety of other therapeutics that we have in this disease today.”
Venetoclax induces cell death in MM cell lines, particularly those positive for t(11;14). The translocation correlates with higher ratios of BCL-2 to MCL-1 and BCL-2 to MCL-2L1 (BCL-XL) mRNA. BCL-2 and MCL-1 promote survival of MM cells.
Study design and enrollment
The phase 1, open-label, multicenter study was designed to determine the best tolerated dose of venetoclax.
Secondary and exploratory objectives included overall response rate (ORR), time to progression, duration of response, and predictive biomarkers.
Patients had to have previously treated MM with measurable disease, ECOG status of 0 or 1, and adequate organ function.
They were excluded if they had an active infection, a history of significant renal, neurologic, psychiatric, endocrine, immunologic, cardiovascular, or hepatic disease within 6 months of study entry, or a history of other active malignancies within 3 years of study entry.
The study called for a 2-week lead-in period of venetoclax with weekly dose escalation. Four different dose cohorts were evaluated—300 mg, 600 mg, 900 mg, and 1200 mg.
Thirty patients were enrolled during the lead-in period, and 36 additional patients enrolled at the maximum evaluated dose of 1200 mg in the safety expansion cohort, for a total of 66 patients.
Patients were treated on a 21-day cycle with daily venetoclax. They could also receive dexamethasone to continue on the study if they progressed while receiving the monotherapy.
Patient characteristics
Patient characteristics were “similar to what you would see in relapsed/refractory multiple myloma,” Dr Kumar said.
Median age was 63 (range, 31–79), and most (62%) were ISS stage II/III.
“I want to draw your attention to two features here,” Dr Kumar said.
“Thirty patients, or 46% of the patients, had 11;14 translocation, and that reflects the interest in this drug for this particular class of patients.”
Twelve patients (18%) had 17p deletion, 32 (48%) had 13q deletion, and 27 (41%) were hyperdiploid.
“What is most striking in this cohort of patients,” Dr Kumar added, “is the fact that the median number of prior lines of therapy was 5, with some as high as 15 prior lines of therapy.”
Seventy percent were refractory to bortezomib, 77% refractory to lenalidomide, and 61% refractory to both. Fifty-two patients (79%) were refractory to their last prior therapy.
Patient disposition
At the time of data cutoff on August 19, 2016, 11 patients (17%) were still active on the study.
The median time on study was 3.3 months (range, 0.2–27), median time on venetoclax monotherapy was 2.5 months (range, 0.2–25), and median time on venetoclax plus dexamethasone was 1.4 months (range, 1–13). Seventeen patients received the combination after disease progression.
Fifty-five patients (83%) discontinued treatment, 41 (62%) because of disease progression, 5 (8%) because of adverse events, 2 (3%) withdrew consent, 1 (2%) was lost to follow-up, and 6 (9%) for unspecified reasons.
The 5 adverse events leading to withdrawal included renal failure (n=2), worsening pulmonary disorder (n=1), paralyzing sciatica (n=1), and shortness of breath and pain (n=1).
“Eight patients died on study,” Dr Kumar said, “none thought to be related to the drug.”
Adverse events
The toxicity profile was primarily hematologic and gastrointestinal.
All patients experienced an adverse event of any grade, and 45 (68%) had a grade 3 or 4 event.
“I wanted to highlight that the majority of the gastrointestinal and non-hematologic toxicity we saw were grades 1 and 2,” Dr Kumar pointed out, “and could be managed symptomatically or with dose modifications.”
Grade 3-4 hematologic adverse events included thrombocytopenia (26%), neutropenia (21%), anemia (14%), leukopenia (14%), and lymphopenia (15%).
Grade 3-4 non-hematologic adverse events included nausea (3%), diarrhea (3%), fatigue (5%), back pain (8%), and vomiting (3%).
Serious adverse events occurring in 2% or more of patients included pneumonia (8%), sepsis (5%), pain, pyrexia, cough, and hypotension (3% each).
Two patients had dose-limiting toxicities of abdominal pain and nausea at the 600 mg dose.
No events of tumor lysis syndrome (TLS) were reported. Dr Kumar explained that this may have been the case because patients thought to be at high risk for TLS were mandated to be in the hospital and observed for early tumor lysis in the initial part of the study.
Response
The ORR was 21% in all patients, including a stringent complete response (sCR) of 3% and a CR of 4%.
“But what was really striking was the response rate that we observed in the 30 patients with translocation 11;14,” Dr Kumar said. “The overall response rate was 40%, with 14% of the patients having complete response or better [stringent CR] and 13% of the patients with very good partial response.”
The 36 patients without t(11;14) had a 6% ORR, 3% sCR, and 3% very good partial response.
“If you look at the response rates based on the type of therapy they were coming off or the drugs they were refractory to, the response rate is very similar across all these patient subgroups, irrespective of what groups of drugs they were refractory to,” he added.
Time to progression for all patients was about 2.5 months. For patients with the translocation, it was about 6.6 months.
“Responses were fairly durable among those who had a response,” Dr Kumar said, “considering these are patients with a median of 5 prior lines of therapy.”
Duration of response for patients with t(11;14) was close to 10 months.
Biomarker analysis
The underlying biology for the response was the BCL-2 to BCL-2L1 ratio, as the investigators had observed in the cell lines.
So they analyzed the BCL-2 gene expression ratio in 24 of the 30 patients with t(11;14).
The investigators used droplet digital PCR performed on CD138-selected bone marrow mononuclear cells collected at baseline.
Nine patients had a high ratio, and their ORR was 88%. Fifteen patients had a low ratio, and their ORR was 20%.
Median time to progression for patients with a high ratio was about 12 months. For those with a low ratio, it was about 9 months.
Median change in M protein for patients with t(11;14) was –53%, compared to +11% in the patients without the translocation.
The investigators recommend additional studies with venetoclax in MM, including those with alternative combination therapies.
Venetoclax is being developed by AbbVie, in partnership with Genentech and Roche. This study was sponsored by AbbVie.
*Data in the abstract differ from the presentation.