Early Study Shows Venetoclax Is Active in Patients With Relapsed/Refractory Myeloma and t(11;14)

Venetoclax, an oral BCL2 inhibitor approved by the U.S. Food and Drug Administration for the treatment of chronic lymphocytic leukemia, may be a treatment option for patients with heavily pretreated multiple myeloma (MM), according to results from a phase I, open-label, dose-escalation study published in Blood.

“Venetoclax has a unique mechanism of action and may offer a novel biologic-driven approach in MM … particularly in patients with the t(11;14) abnormality,” wrote Shaji Kumar, MD, from the Mayo Clinic in Rochester, Minnesota, and co-authors.

Enrollment in the ongoing trial began in October 2012 with 66 patients (median age = 63 years; range = 31-79 years) included as of data cutoff (August 19, 2016): 30 patients in the dose-escalation phase and 36 in the safety-expansion phase.

Patients were eligible for inclusion if they had received at least one prior MM therapy (including a proteasome inhibitor or immunomodulatory drug). Patients with an active infection, history of significant medical illness within the past six months, or history of other active malignancies within the past three years were excluded.

Patients had received a median of five prior therapies (range = 1-15 therapies), and most (61%) had disease refractory to both bortezomib and lenalidomide. Thirty patients (46%) were positive for t(11;14). “Although the study did not select for t(11;14) myeloma,” the authors explained, “a high proportion of patients with this abnormality were enrolled … based on previously available data showing activity of venetoclax in t(11;14)-positive myeloma cells.”

After a two-week lead-in period with weekly dose escalation to minimize the risk of tumor lysis syndrome, venetoclax was administered daily at 300, 600, 900, or 1,200 mg in the dose-escalation phase of the study and at 1,200 mg in the safety-expansion phase – all in 21-day cycles.

Two patients experienced dose-limiting toxicities at the 600 mg dose, both of which resolved after venetoclax was discontinued. At data cutoff, the maximum tolerated dose (primary endpoint) was not reached and 1,200 mg was recommended for phase II dosing.

The median time on study was 3.3 months (range = 0.2-27 months), with a median time on venetoclax monotherapy of 2.5 months (range = 0.2-25 months). Patients with t(11;14) had a longer time on study and venetoclax monotherapy (7.8 months; range = 0.4-25 months; p value not provided), the authors observed.

Most patients discontinued treatment (n=55; 83%) because of disease progression (n=42), adverse events (AEs; n=5), withdrawal of consent (n=2), or loss to follow-up (n=1). (The remaining reasons for discontinuation were not specified.) Eight patients died because of disease progression (n=6), lung disorder (n=1), or brain hemorrhage following trauma (n=1). At the time of reporting, 11 patients were still on study (including 8 with t[11;14]).

All patients experienced at least one AE, the most common of which “were mild to moderate gastrointestinal toxicities [including nausea, diarrhea, and vomiting] and grade 3/4 hematologic toxicities, which were manageable and did not result in study drug discontinuation,” the authors wrote. The most common grade 3/4 AEs were thrombocytopenia (26%), neutropenia (21%), anemia (14%), and leukopenia (14%). Serious AEs (occurring in ≥2 percent of patients) included pneumonia (8%), sepsis (5%), cough (3%), hypotension (3%), pain (3%), and pyrexia (3%).

Among all patients, the overall response rate (ORR) was 21 percent (n=14), including a very good partial response or better (≥VGPR) in 10 patients (15%). Nearly all of these responses (n=12) occurred in the 30 patients with t(11;14), the researchers reported, for an ORR of 40 percent in this cohort (including 1 stringent response, 3 complete responses, and 4 VGPRs).

The median duration of response (DOR) was similar in the overall patient population and for those with t(11;14): 9.7 months (95% CI 7.0 – not reached) and 9.7 months (95% CI 6.3 – not reached; p value not provided), respectively. However, the time to progression (TTP) was longer among those with t(11;14): 6.6 months (95% CI 3.9-10.2) versus 2.6 months (95% CI 1.9-4.7; p value not provided), respectively.

Seventeen patients experienced disease progression while receiving venetoclax monotherapy, including nine with t(11;14). Per study protocol, these patients could receive dexamethasone plus venetoclax and remain on study; one patient had a partial response (PR), six had stable disease, nine progressed, and one discontinued the study before assessment. “The addition of dexamethasone at the time of progression did not … add any clinical benefit for patients on venetoclax monotherapy,” the authors reported.

The researchers also conducted gene-expression analyses of baseline bone marrow aspirate samples (evaluable in 44 patients) to identify biomarkers predictive of response to venetoclax. Within this group of patients, 10 had higher BCL2:BCL2L1 ratios and, the authors added, “as expected, this favorable BCL2 profile was more frequent in the t(11;14) than in the non-t(11;14) subgroup (38% vs. 5%, respectively; p value not provided).”

Eight of these patients (all of whom had t[11;14]) achieved a PR or better, with a median duration of response of 9.7 months (range not provided). The median TTP was 11.5 months (range not provided) in all 10 patients with a high BCL2:BCL2L1 ratio. Three patients (9%) with a low BCL2:BCL2L1 ratio achieved a PR or better, with a median DOR of 7.8 months (range not provided). The median TTP in this cohort was just 1.9 months (range not provided).

“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,” the authors concluded. “[Our findings] raise the possibility that future myeloma therapy may be driven by the underlying genetic abnormality or another surrogate biomarker.”

The study is limited by its small patient population and lack of a comparator arm.

AbbVie and Genentech, manufacturers of venetoclax, provided financial support for the study.

The authors report research funding from AbbVie and Genentech.


Kumar S, Kaufman JL, Gasparetto C, et al. Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood. 2017 October 10. [Epub ahead of print]