Dr. Shaji Kumar
Mayo Clinic
Rochester, MN, USA

Background: The anti-apoptotic protein BCL-2 has been implicated in mediating the survival of MM cells. Venetoclax (VEN) is a potent, selective, orally bioavailable small-molecule BCL-2 inhibitor. VEN induces cell death in MM cell lines and primary samples in vitro, especially in t(11;14)-positive (pos) cells, which express a high ratio of BCL2 to MCL1(VEN resistance factor). The current Ph 1 study evaluates safety and efficacy of VEN in pts with R/R MM.

Methods: Primary objectives are to evaluate safety, PK, and RPTD; other objectives include preliminary efficacy and impact of chromosomal abnormalities. In dose-escalation cohorts, VEN was given PO daily at 300, 600, 900, or 1200 mg after a 2-week dose ramp-up. Pts were monitored for tumor lysis syndrome (TLS).

Results: As of 12/19/2014, there were 28 pts with median age 65 (12/16 F/M); 9 ISS stage I, 11 stage II, 6 stage III. Median (range) prior therapies: 6 (1–13). 23 had prior bortezomib (15 refractory), 26 lenalidomide (12 refractory), and 13 auto-HSCT. 10 pts were t(11;14)-pos. AEs in ≥20% pts: diarrhea (32%), nausea (32%), neutropenia (21%), fatigue (21%). Grade 3/4 AEs (≥10%): thrombocytopenia (18%), anemia (14%), neutropenia (14%). 7 pts had SAEs, with 1 (epigastric pain) possibly related to VEN. 17 pts have discontinued (D/C): 14 due to PD, 2 for AEs (worsening shortness of breath, hypokalemia), and 1 withdrew consent; 11 still receiving therapy. 2 deaths occurred (both PD). 2 DLTs were seen at 600 mg (cohort was expanded): epigastric pain, nausea with abdominal pain. No pt had TLS. Preliminary PK (n=11; 300 and 600 mg): mean Cmax and AUC24 were ~dose-proportional with high intra-dose variability. 21 of 28 pts were evaluable for preliminary efficacy. Best response by t(11;14) status shown in Table.

Conclusions: VEN monotherapy was well tolerated in heavily-pretreated R/R MM. Responses (including CR) and longer ToS were observed in t(11;14)-pos pts. RPTD was achieved; study is now enrolling in the safety expansion cohort at 1200 mg (with 2-week ramp-up). Clinical trial information: NCT01794520


Dr. Shaji Kumar is the Medical Director for the Cancer Center Clinical Research Office at the Mayo Clinic Cancer Center in Rochester, Minnesota. Dr. Kumar holds membership in several professional organizations including the American Society of Hematology, American Society of Clinical Oncology, American Association for Cancer Research, American Society of Blood and Marrow Transplantation, the Association of Physicians of India, and the European Hematology Association. He has published numerous articles, abstracts, editorials, and letters in the peer-reviewed literature, including Blood, Journal of Clinical Oncology, Leukemia, American Journal of Hematology, British Journal of Haematology, and Bone Marrow Transplantation. Visit Dr. Shaji Kumar’s full biography.

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