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Venetoclax demonstrates activity in multiple myeloma
Venetoclax monotherapy showed activity among patients with relapsed or refractory multiple myeloma, particularly those with t(11;14) and favorable BCL2 family profile, according to study results published in Blood.
Venetoclax (Venclexta; AbbVie, Genentech) — a potent, selective, orally bioavailable BCL02 inhibitor — has shown promising antitumor activity in chronic lymphocytic leukemia, acute myeloid leukemia and non-Hodgkin lymphoma.
“Despite advances in new and effective treatment strategies, multiple myeloma remains incurable, with inevitable relapse in the majority of patients,” Shaji Kumar, MD, professor of medicine in the division of hematology at Mayo Clinic in Rochester, Minnesota, and colleagues wrote. “Development of novel agents with a unique mechanism of action that are active in relapsed/refractory multiple myeloma will expand options for patients.”
In the phase 1 M13-367 study, Kumar and colleagues treated 66 patients (median age, 63 years) with relapsed or refractory multiple myeloma in a dose escalation cohort (n = 30) — with daily venetoclax at 300 mg, 600 mg, 900 mg or 1,200 mg after a 2-week lead-in — or a safety expansion cohort (n = 36), with 1,200 mg daily venetoclax. Dexamethasone could be added during treatment.
Patients had received a median of five (range, 1-15) prior therapies. Sixty-one percent of patients were refractory to both bortezomib (Velcade, Takeda Oncology) and lenalidomide (Revlimid, Celgene). Forty-six percent of patients were positive for t(11;14).
The overall response rate was 21% (n = 14), and 15% had very good partial response or better.
Most responses (86%) occurred among patients with t(11;14). Among patients with this translocation, ORR was 40% and 27% achieved very good partial response or better.
Overall, median duration of response was 9.7 months (95% CI, 7-not reached) for all patients and 9.7 months (95% CI, 6.3-not reached) for those with t(11;14).
Median time to progression was 2.6 months (95% CI, 1.9-4.7) overall, but was longer among patients with t(11;14) (6.6 months vs. 1.9 months).
Gene expression analysis showed ratios of BCL2:BCL2LI and BCL2:MCL1 appeared significantly higher among patients who achieved overall response to venetoclax.
The most common adverse events included nausea (47%), diarrhea (36%) and vomiting (21%).
The most common grade 3 or grade 4 events included thrombocytopenia (32%), neutropenia (27%), anemia (23%) and leukopenia (23%).
Eleven patients remained on the study; 55 discontinued the study, including 42 for disease progression and five for adverse events. Three patients required dose reductions because of adverse events, and 20 required temporary interruption of therapy because of adverse events.
Researchers did not define a maximum-tolerated dose.
Seventeen patients — nine of whom harbored t(11;14) — added dexamethasone after disease progression.
Eight deaths occurred, six of disease progression, one resulting from lung disorder and one resulting from brain hemorrhage after trauma.
“Despite many advances, at this time, there are no biologic-based therapeutic approaches in the management of [multiple myeloma],” the researchers wrote. “Given the multiple available drugs and combination regimens in this disease, predictive markers to guide selection of therapy would be a key advancement in the care of these patients, delivering the most effective treatment to the right patients. The findings of the current study are commensurate with preclinical findings and raise the possibility that future myeloma therapy may be driven by the underlying genetic abnormality or another surrogate biomarker.” – by Cassie Homer
Disclosures: Kumar reports research funding from AbbVie, Celgene, Janssen, Millennium/Takeda, Novartis, Onyx and Sanofi; consultant roles with Bristol-Myers Squibb, Celgene, Janssen, Millennium, Noxxon Pharma and Onyx; and honorarium from Skyline. Please see the full study for all other authors’ relevant financial disclosures.