Efficacy of Venetoclax Based Regimens in Relapsed Refractory Multiple Myeloma: A Systematic Review and Meta-Analysis
Authors: Hashim Laila , Faisal Muhammad Salman , Ahmed Zahoor , Selene Insija Ilyas , Shahzad Moazzam , Abdullah Syed Maaz , Samhouri Yazan , Yasir Muhammad , Wahab Ahsan , Ehsan Hamid , Neupane Karun , Anwer Faiz , Fazal Salman 
Published: November 2020

Background:
Clonal plasma cells in multiple myeloma (MM) over express b-cell lymphoma-2 protein (BCL2). Which is the target for venetoclax (VEN). VEN has a promising efficacy and a favorable safety profile in MM patients. This review highlights the efficacy of VEN for the treatment of relapsed refractory (RR) MM.
Methodology:
We performed a comprehensive database search on four major databases(PubMed, Embase, Cochrane, and Clinical trials.gov). Our search strategy included MeSH terms and keywords for multiple myeloma and VEN, including trade names and generic names, from the date of inception of the database to April 2020.The initial search revealed 782 articles. After excluding review articles, duplicates, and non-relevant articles,we included six studies(four clinical trials and two retrospective studies), which reported an overall response rate (ORR) in RRMM patients. Proportions along with 95% Confidence Interval (CI) were extracted to compute pooled analysis using the 'meta' package by Schwarzer et al. in the R programming language (version 4.0.2) to report the efficacy of VEN. We pooled the results of the experimental arms of included trials using the inverse variance method and logit transformation. Between studies,the variance was calculated using Der Simonian-Laird Estimator.
Results:
We identified 568 patients from four clinical trials [Moreau et al.2019, the BELLINI trial, (n=291, venetoclax arm= 194, placebo arm= 97)], Costa et al. 2018 (n=42), Kumar et al. 2017(n=66), and Moreau et al. 2017 (n=66)] and two retrospective studies (Kambhampati et al. 2020 (n= 47) and Sidiqi et al.2019 (n=56)). Among which 563 patients were evaluable for the treatment outcomes. One hundred and forty two patients (25%) had t(11:14)mutation. The median age of the patients ranged from 64-66 years, and the median number of prior therapies was ≥2. The median dose of venetoclax ranged from 50 mg/day to 1200 mg/day in dose-escalation cohorts of clinical trials while in the retrospective study by Kambhampati, S et al., the median dose of venetoclax was 800 mg/day. The pooled overall response rate (ORR) for all patients who received venetoclax (n=466) was 57% (95% confidence interval (CI) 0.34-0.77, p&lt;0.01; I2=95%), with the highest rates of 84% and 79% being reported from phase III trial using VEN + bortezomib (V) + dexamethasone (d) by Moreau et al.(2019), and VEN + carfilzomib + d in phase II clinical trial by Costa et al. (2018), respectively (Figure 1A). A minimum ORR of 21% was observed in a retrospective study by Siddiqi et al. (2019). Among 142 patients with positive t(11:14) in all studies, ORR was 56% (95% CI 0.44-0.68, p&lt;0.11; I2=44%) (Figure 1B) with the highest rate of 100% being reported from Costa et al., though the number of patients was small. Among 362 patients with no t(11:14) ,ORR was 33% (95% CI 0.16-0.55, p&lt;0.01: I2=89%), with the highest rate of 56% being reported from Moreau et al. in a phase III trial using VEN-Vd (Figure 1C). The highest median duration of response (DOR) (23.4 months) was reported with combination therapy of VEN-Vd. Two hundred and thirty eight (42%) of the patients discontinued VEN, among whom 132 (55%) were reported to have progressive disease. The most common grade≥3 hematological adverse effects were neutropenia, thrombocytopenia, and anemia. The gastrointestinal distress was the most common non-hematological toxicity reported in all the studies. Sixty four (33%) patients died on VEN arm vs. 24 (25%) on placebo in the BELLINI trial, the trend of OS is non-significantly better in VEN arm in t(11:14) while OS is non-significantly worse in non t(11:14) group.
Conclusion:
VEN is an effective treatment option for relapsed and refractory multiple myeloma patients with t(11:14) translocation. The overall response rate and the duration of response are better in patients with t(11:14). The CANOVA trial is ongoing now to better answer the debatable question of VEN efficacy in t(11;14) MM patients.

Disclosures
Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau. Fazal:Jansen: Speakers Bureau; Stemline: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Gilead/Kite: Consultancy, Speakers Bureau; Glaxosmith Kline: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Incyte Corporation: Consultancy, Honoraria, Speakers Bureau; Karyopham: Speakers Bureau; Celgene: Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharma: Consultancy, Speakers Bureau.