Phase I Study Shows Venetoclax Active in Patients With Relapsed/Refractory Myeloma

The B-cell lymphoma/leukemia-2 (BCL-2) inhibitor venetoclax may be a new option for patients with heavily treated multiple myeloma (MM), according to results from an open-label, phase I trial presented at the 2016 ASH Annual Meeting, in which treatment with the drug led to an overall response rate (ORR) of 21 percent. Shaji Kumar, MD, from the Division of Hematology at the Mayo Clinic in Rochester, Minnesota, and co-authors also found that patients with t(11;14) had higher response rates and longer durations of response, compared with patients without the translocation.

Together with the “acceptable and well tolerated” safety profile, Dr. Kumar reported that “the results are encouraging enough that additional studies are planned, especially alternative combinations.”

The researchers enrolled 66 patients with relapsed/refractory MM (median age = 63 years; range = 31-79 years): 30 patients were in the dose-escalation phase and 36 were in the safety-expansion phase. Most patients (n=39; 62%) had International Staging System II/III disease. Patients were heavily pretreated, having received a median of five prior therapies (range = 1-15 therapies), mostly bortezomib (n=62; 94%), lenalidomide (n=6; 94%), and autologous hematopoietic cell transplantation (n=50; 76%).

After a two-week lead-in period with weekly dose escalation, venetoclax was administered daily at 300, 600, 900, or 1,200 mg in the dose-escalation phase and at 1,200 mg in the safety-expansion phase, all in 21-day cycles. If patients progressed while receiving venetoclax monotherapy, they could receive venetoclax plus dexamethasone and continue the study.

Fifty-one patients (77%) discontinued the study for the following reasons: disease progression (n=39), adverse events (AEs) or toxicity (n=5), consent withdrawal (n=2), lost to follow-up (n=1), or reasons not specified (n=4).

The most common all-grade AEs were nausea (48%), diarrhea (36%), neutropenia (32%), thrombocytopenia (32%), fatigue (27%), anemia (23%), back pain (21%), and vomiting (21%). Grade 3/4 AEs included thrombocytopenia (26%), neutropenia (20%), lymphopenia (15%), anemia (14%), and leukopenia (12%). Serious AEs included pneumonia (8%), sepsis (5%), pain, pyrexia, cough, and hypotension (3% each). No events of tumor lysis syndrome were observed.

Eight patients died during the study: six due to disease progression, one due to a lung disorder, and one due to a brain hemorrhage following injury. None of the deaths was considered treatment-related.

After a median of 2.5 months (range = 0.2-23 months), the ORR was 21 percent (n=14), including two complete responses (CRs), two stringent CRs, and six very good partial responses (VGPRs). The median duration of response and time to progression was 9.7 months (range = 1-22 months) and 2.6 months
(range = 1-23 months), respectively.

Notably, responses were more common and deeper in the 30 patients with t(11;14) MM, Dr. Kumar and researchers observed. The ORR in that cohort increased to 40 percent (n=12), including eight patients who achieved a VGPR or better. “Venetoclax activity in t(11;14) myeloma was independent of refractory status to prior therapies,” Dr. Kumar said, adding that “patients who achieved at least minimal response in the t(11;14) group had a median of four prior therapies and were mostly refractory to bortezomib, lenalidomide, or both (71%).”

Venetoclax was even more effective in a smaller subgroup of nine patients with t(11;14) and a high BCL-2:BCL2L1 ratio, compared with patients with a low BCL-2:BCL2L1 ratio (ORR=88% vs. 20%; p value not provided). “I think we have a drug that can change the outcome for a lot of patients with myeloma,” Dr. Kumar said. “It may be the first drug that is actually going to be a biomarker-driven drug in this disease.”

The study is limited by the small study population and the potential effect of adding dexamethasone to venetoclax monotherapy for patients who progressed. Also, though there appeared to be improved response rates in the t(11;14) population, the study did not report p values, so the significance of the comparisons is unknown.


Kumar S, Vij R, Kaufman JL, et al. Venetoclax monotherapy for relapsed/refractory multiple myeloma: safety and efficacy results from a phase I study. Abstract #488. Presented at the 2016 ASH Annual Meeting, December 4, 2016; San Diego, California.