Venetoclax monotherapy for RRMM patients with t(11;14)

The translocation t(11;14), occurring in around 15-20% of Multiple Myeloma (MM) patients, has been linked with higher than average levels of BCL2 mRNA expression levels, in comparison with MCL1 and BCL-X_L. These patients are good candidates for targeted therapy with venetoclax (ABT-199), a selective BCL-2 inhibitor leading to cell death in MM cells.

In a phase I trial to treat Relapsed and Refractory Multiple Myeloma (RRMM) patients, venetoclax monotherapy was assessed - the primary objective to evaluate the safety profile and pharmacokinetics, and to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Secondary objectives were to assess the overall response rate (ORR), time to progression (TTP), duration of response (DOR), and exploratory biomarkers.

The results of the study, conducted by Shaji Kumar, from the Mayo Clinic, Rochester, MN, USA, and in collaboration with a large group of researchers, were reported in Blood in October 2017. The Phase I M13-367 study recruited patients with RRMM from October 2012; data cut-off was 19 August 2016.

Study Design and safety:

• Patients (pts) n = 66 with RRMM were enrolled; dose-escalation = 30, safety expansion = 36
• Venetoclax adinistered orally once daily at 300, 600, 900, or 1200 mg in dose-escalation cohorts and 1200 mg in the safety expansion
• Median age = 63 years (range 31-79); median number of prior therapies = 5 (range 1-15); t(11;14) positive = 30 pts, 5/30 also had chromosome 17p deletion, 11 had chromosome 13q deletion, and 8 were hyperdiploid
• Median study time = 3.3 months (range: 0.2–27); median time on venetoclax monotherapy = 2.5 months (range: 0.2–25) and t(11;14) group = 7.8 months (range: 0.4–25)
• Dexamethasone was added after disease progression for 17 pts (9 with t(11;14)), and median time on venetoclax plus dexamethasone = 1.4 months (range: 0.1–13)
• Discontinuation = 55 pts; due to disease progression = 42 pts, AEs = 5 pts, consent withdrawn = 2 pts, lost to follow-up = 1 pt and unexplained = 5 pts
• Deaths = 8 pts; due to disease progression = 6, unrelated complaints = 2
• All pts reported at least 1 Adverse Effect (AE); commonly moderate gastrointestinal toxicities
• Most common grade 3 or 4 AEs: thrombocytopenia = 26%, neutropenia = 21%, anemia = 14%, and leukopenia = 14%
• No major differences in safety events were observed for different doses and the MTD was not reached
• The safety expansion proceeded with a dose of 1200 mg daily as the planned MTD

Results:

• Overall Response for all pts (partial response (PR) or better) = 21% (14/66 pts)
• Very good partial response or better (≥VGPR) = 15% (10 pts)
• t(11;14) group (n = 30): ORR = 40%; ≥VGPR = 27% (stringent complete response (sCR) = 1 pt, CR = 3 pts, VGPR = 4 pts)
• Median duration of response (DOR) = 9.7 months (pts with t(11;14) and non-t(11;14))
• Median TTP: non-t(11;14) = 1.9 months (95% CI: 1.2, 2.3)  vs t(11;14) = 6.6 months (95% CI: 3.9, 10.2)
• Median TTP: t(11;14) who achieved PR = 8.6 months and ≥VGPR =  11.5 months
• ORR via number of lines of prior therapy: 1–3 = 22% (2/9) and ≥4 = 48% (10/21)
• Pts with t(11;14) who achieved clinical benefit (minimum response or better) = 14 (3/14 = 17p chromosome deletion, 2/14 = chromosome 13q deletion, and 4/14 = hyperdiploid)
• Gene expression analysis of baseline BM aspirates from 44/47 pts were evaluated; ratios of BCL2:BCL2L1 and BCL2:MCL1 were significantly higher in pts who achieved an OR (≥PR vs <PR) to venetoclax
• Rank order of expression profiles that best correlated with response: High BCL2:BCL2L1 > Low BCL2L1 > High BCL2:MCL1 > High BCL2 > Low MCL1
• A threshold value of BCL2:BCL2L1 = log2 ≥ 2.3; P <0.01 was found to enable selection of pts most likely to respond to venetoclax
• High BCL2:BCL2L1 expression ratio = 10/44 pts (23%); t(11;14) = 9/24 pts (38%) vs non-t( 11;14) = 1/20 (5%)
• Out of these 10 pts, PR or better = 8 pts (all t(11;14) positive), median DOR = 9.7 months; median TTP = 11.5 months
• Low BCL2:BCL2L1 expression ratio = 3/34 pts (all t(11;14) positive) achieved a PR or better; median DOR = 7.8 months
• Median TTP in pts with a low BCL2:BCL2L1 ratio: non-t(11;14) pts = 1.9 months vs t(11;14) pts = 5.3 months
• Pts with t(11;14) and high BCL2:BCL2L1 expression: PR or better = 8/9 (88%); Median DOR = 9.7 months; Median TTP = 11.5 months

Conclusion

A daily dose of 1,200 mg of venetoclax was well-tolerated in heavily pre-treated RRMM patients, and in particular promising efficacy data was observed for t(11;14) positive patients. Analysis of baseline BM aspirates also indicated that patients with high BCL-2 expression and lower levels of BCL-X_L/MCL responded more effectively to venetoclax, and as predicted this profile of expression was more frequent in the t(11;14) sub-group. Although this monotherapy was effective, it is more commonly used with dexamethasone, which increases the BCL-2 dependency of myeloma cells. Ongoing trials are testing this combination, along with a PI as a triplet regimen, and it will be interesting to see sub-group analyses for t(11;14) positive patients. Overall, this research beckons further patient pre-screening ahead of drug selection, as targeted therapy slowly becomes mainstream.