Phase I venetoclax monotherapy for relapsed/refractory multiple myeloma.

Abstract

8032 Background: The anti-apoptotic protein BCL-2 has been implicated in the survival of multiple myeloma (MM) cells. Venetoclax (VEN) is an oral, highly selective BCL-2 inhibitor, which induces cell death in MM cell lines and primary samples, particularly those with t(11;14), a high BCL-2 and low BCL-XL profile. Methods: In this phase 1 study of VEN monotherapy in relapsed/refractory (R/R) MM, objectives are to evaluate safety, PK, RPTD, and preliminary efficacy. After 2-week dose-ramp-up, VEN was given daily at 300, 600, 900, or 1200 mg in dose escalation (DE) cohorts and 1200 mg in safety expansion (SE). Results: As of 9/17/15, 48 pts were enrolled: 30 DE and 18 SE. Median age was 65; 28 were ISS stage II/III. Median (range) prior therapies: 5 (1–15). 45 had prior bortezomib (32 refractory), 46 lenalidomide (37 refractory), and 40 had SCT. 18 pts had t(11;14). AEs in ≥ 30% of pts were diarrhea (40%), nausea (40%), thrombocytopenia (31%). Grade 3/4 AEs in ≥ 10%: thrombocytopenia (29%), anemia, neutropenia (17% each). SAEs in ≥ 2 pts were sepsis (n = 3), cough, malignant neoplasm progression, and pyrexia (2 each). Median (range) time on VEN was 1.9 (0.2–13.8) months. 33 (69%) pts discontinued (DC): 26 related to PD, 4 due to AEs (worsening shortness of breath, hypokalemia, nausea, lung disorder), 2 withdrew consent, 1 due to death (brain hemorrhage following injury). 5 deaths occurred (3 PD, 1 brain hemorrhage, 1 lung disorder). 2 DLTs were seen at 600 mg (cohort was expanded): epigastric pain, nausea with abdominal pain. Steady state mean Cmax and AUC24 were ~dose proportional at all doses except 900 mg (n = 21). 43 of 48 pts were evaluable for efficacy (table). In CR pts, responses were maintained for 9.7 (600 mg) and 9.0 months (900 mg, ongoing). VGPR was reported for 3 pts, all 1200 mg. Conclusions: VEN monotherapy has a tolerable safety profile in R/R MM. Preliminary efficacy, including CR, and VGPR, support VEN single agent activity in this population, primarily in t(11;14) pts. Clinical trial information: NCT01794520.Best response, n (%) With t(11;14) (n = 17) Without t(11;14) (n = 26) All (n = 43) ORR 4 (24) 1 (4) 5 (12) CR 2 (12) 0 2 (5) VGPR 2 (12) 1 (4)* 3 (7) MR 1 (6) 0 1 (2) SD 5 (29) 12 (46) 17 (40) PD 6 (35) 12 (46) 18 (42) DC before assessment 1 (6) 1 (4) 2 (5) *Pt has translocation of chromosome 14 with unknown partner