Efficacy and Safety Profile of Ixazomib Based Regimens in Relapsed/Refractory Multiple Myeloma: A Meta-Analysis of Clinical Trials
Authors: Iftikhar Ahmad , Ali Muhammad Ashar , Javaid Anum , Abu Zar Muhammad , Sohail Atif , Razzaq Faryal , Usman Rana M , Anwar Muhammad Yasir , Hassan Hamza , Anwer Faiz 
Published: November 2020

Background:
Multiple myeloma (MM) is an incurable disease, and clinical trials with newer agents have shown improved patient outcomes. There is a need for effective and tolerable treatment for patients with relapsed/refractory MM (RRMM). Proteasome inhibitors (bortezomib, carfilzomib, ixazomib) remain an integral part of regimens used in RRMM or newly diagnosed (ND) MM. This meta-analysis aims to assess the efficacy and safety of ixazomib (Ixa) based regimens in RRMM.
Methods:
A comprehensive literature search was performed on PubMed, Cochrane, Embase, Web of Science, and clinicaltrials.gov. We used MeSH and Emtree terms, "ixazomib" AND "multiple myeloma" from the inception of literature till 06/01/2020. We screened 1529 articles and included 3 randomized clinical trials (RCT, N=907) and 8 non-randomized clinical trials (NRCT, N=321). We excluded case reports, case series, review articles, meta-analysis, observational studies, and clinical trials that didn't provide data about the efficacy and safety of Ixa in RRMM. We used the R programming language (version 4.0.2) to conduct a meta-analysis.
Results:
In 11 clinical trials (N=1228), the age range of patients was 30-91 years. In Phase III RCTs (N=837) comparing Ixa + Lenalidomide (Len) + dexamethasone (Dex) vs. placebo + Len + Dex, risk ratio of overall response rate (ORR), complete response (CR), and very good partial response (VGPR) were 1.14 (95% CI=1.05-1.24, I2=80%), 1.87 (95% CI=1.17-2.99, I2=0), and 1.15 (95% CI=0.95-1.40, I2=0), respectively in favor of Ixa + Len + Dex. (Fig 1-3) Grade 3 or higher treatment-related adverse events (TRAEs) thrombocytopenia, diarrhea, and rash were reported in 20%, 5.7% and 6.4% of the patients in the Ixa group vs. 10%, 2.1%, and 2.8% in the placebo group, respectively. In a Phase II RCT by Kumar et al (N=70) comparing the Ixa dosage, 4 mg Ixa + Dex yielded an ORR of 31%, CR 2.8%, and VGPR 17.1%, while 5.5 mg Ixa yielded improved ORR of 54%, CR 2.8%, and VGPR 25.7%.
In a NRCT by Costello et al. (N=6), Ixa + daratumumab (Dara) + Pom + Dex yielded 100% ORR, CR 5% (95% CI=0.17-0.83), and VGPR 50% (95% CI=0.17-0.83). ≥Grade 3 TRAEs were hypertension (16%), and hematological (33%). Among 417 patients from two RCT in single arm who received Ixa + Len + Dex, pooled ORR was 70% (95% CI=0.53-0.82, I2=84%), pooled CR 11% (95% CI=0.8-0.14, I2=0), and pooled VGPR was 29% (95% CI=0.18-0.43, I2=66%). In a NRCT by Dhakal et al. (N=19), Ixa + bendamustine + Dex yielded an ORR 58% (95% CI=0.36-0.77), CR 0, and VGPR 11% (95% CI =0.03-0.34). ≥Grade 3 TRAEs were neutropenia 31%, thrombocytopenia 52%, and diarrhea 10%. In 2 NRCT (N=106), Ixa + cyclophosphamide (Cyc) + Dex yielded a pooled ORR 52% (95% CI=0.42-0.61, I2=0), CR 4% (95% CI=0.01-0.10, I2=0), and VGPR 17% (95% CI=0.11-0.25, I2=0). ≥Grade 3 TRAEs were thrombocytopenia (15%), and upper abdominal pain (4%). In a NRCT by Ludwig et al. (N=90), Ixa + thalidomide (Thal) + Dex yielded an ORR 51% (95% CI=0.41-0.61), CR 9% (95% CI=0.5-0.17), and VGPR 14% (95% CI=0.09-0.23). ≥Grade 3 TRAEs were anemia (17.8%), and infections (16.1%). In a NRCT by Krishnan et al. (N=31), Ixa + Pomalidomide (Pom) + Dex yielded an ORR 48% (95% CI=0.32-0.65) and VGPR 16% (95% CI=0.07-0.33). (Fig 4-6) ≥Grade 3 TRAEs were neutropenia (10%), and lymphopenia (35%).
In 2 NRCT by Kumar et al. (N=70) of two drugs combination, Ixa + Dex yielded a pooled ORR 43% (95% CI=0.28-0.59, I2=47%), pooled CR 1% (95% CI=0-0.09, I2=0), and pooled VGPR 24% (95% CI=0.16-0.36, I2=0). ≥Grade 3 TRAEs were hematological (28%), and non-hematological (22.8%). In 2 NRCT of Ixa monotherapy (N=69), pooled ORR was 17% (95% CI=0.10-0.28, I2=0), and pooled CR 6% (95% CI=0.2-0.22, I2=0). (Fig 4-6) ≥Grade 3 TRAEs were anemia (11%), thrombocytopenia (5.4%), and neutropenia (2.7%).
Conclusion:
Our study provides useful insight into relative efficacy of various Ixa regimens for the treatment of RRMM. The pooled analysis of RCT showed that the combination of Ixa + Len + Dex yielded better response as compared to placebo. In the pooled analysis of outcomes in single arm NRCT, Ixa + Dara + Pom + Dex and Ixa + Len + Dex showed better efficacy outcomes as compared to Ixa + Dex in combination with Thal, Cyc, or Bendamustin. Three drugs Ixa combination regimens had better efficacy as compared to two drugs combination of Ixa + Dex and Ixa monotherapy. Ixa was well tolerated with acceptable safety profile. Additional multicenter, double-blind clinical trials are needed to confirm these results.

Disclosures
Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.