Safety and Efficacy of Venetoclax in Relapsed Refractory Multiple Myeloma: A Systematic Review and Meta-Analysis
Authors: Durer Ceren , Durer Seren , Ijaz Awais , Kamal Ahmad , Abu Zar Muhammad , Rafae Abdul , Malik Mustafa Nadeem , Khan Ali Younas , Usman Muhammad , Selene Insija Ilyas , Tariq Muhammad Junaid , Fraz Muhammad Asad , Jose Jemin Aby , Anwer Faiz 
Published: October 2019

Abstract
Background:
Management of relapsed or refractory multiple myeloma (RRMM) is challenging. Venetoclax (ABT-199) is an oral selective inhibitor of an anti-apoptotic protein Bcl-2 that showed activity in preclinical studies, especially for t(11;14) MM cell lines or in the cells with high bcl-2 expression. We conducted a systematic review and meta-analysis to evaluate the outcomes of venetoclax in RRMM.
Method:
Literature databases (Medline, Embase, and Cochrane) were searched for studies published up to June 19, 2018. Our search strategy included MeSH terms and key words for multiple myeloma and venetoclax including trade names and generic names. CMA software v.3 was used for analysis. Random-effects model was applied.
Results:
163 patients (n=115 in dose escalation, n=48 in safety expansion) were identified from two clinical trials (phase Ib study by Moreau, P. et al. 2017, n=66 and phase I/II study by Kumar, S. et al. 2017, n=66) and one retrospective study (Galligan, D. et al. 2017, n=31). The median age was 63, 64, N/A in phase Ib, phase I/II and retrospective study, respectively. 47 patients (29%) had t(11;14). Other cytogenetic aberrations were del(17p) [n<25]; t(4;14) [n=5]; del(13q) [n=41]; t(14;16) [n<5]; t(14;20) [n<5]. 124 patients (76%) were refractory to bortezomib and/or lenalidomide; most patients had ≥3 prior therapies. Venetoclax doses escalated from 50 mg/day to 1200 mg/day in phase Ib and phase I/II studies. Safety expansion doses were 800 mg and 1200 mg in phase Ib and phase I/II studies, respectively. Median dose of venetoclax for the retrospective study was 800 mg daily. Bortezomib and dexamethasone doses from phase Ib study were 1.3 mg/m2 subcutaneous and 20 mg, respectively. The median duration on venetoclax and median time on study ranged from 2 to 6 months. Median duration of response (DOR) and median time-to-progression (TTP) were reported higher with combination therapy of bortezomib and dexamethasone (9.7 months and 9.5 months, respectively). 62% of patients have discontinued the therapy due to: progressive disease (48%), adverse events (6%), and various other reasons (8%). There were 13 deaths; 6 were due to disease progression. Most common side effect from three studies was gastrointestinal problems such as nausea, diarrhea and vomiting. The median duration of response was 9.7, 9.7, 2 months and the median time to progression was 9.5, 2.6, NA months for phase Ib, phase I/II and retrospective study, respectively. The pooled overall response rate (ORR) for all patients was 43% (n=163) with the highest rate (67%) being reported from phase Ib study using combined venetoclax, bortezomib and dexamethasone (Figure 1 and 2). Among 44 patients with t(11;14), ORR was 40% and 78% in phase I/II and phase Ib studies, respectively. Twenty-eight patients who expressed high-bcl2 showed ORR rates of 80% and 94%, whereas 50 patients who had low-bcl2 level showed ORR rates of 8% and 59% in phase I/II and phase Ib studies, respectively (Table 1).
Conclusion:
Single-agent venetoclax showed an ORR of 21%, the addition of bortezomib produced an ORR of 32%, and the addition of bortezomib and dexamethasone improved an ORR to 67%. Better ORR was observed in patients with t(11;14) and with high-bcl2 expression. The highest median DOR (9.7 months) and TTP (9.5 months) were reported with a combination therapy of venetoclax, bortezomib and dexamethasone. Most reported adverse events were related to gastrointestinal system. More clinical studies evaluating the combination therapies using venetoclax are needed.

Disclosures
No relevant conflicts of interest to declare.