Evaluation of Efficacy and Safety of Front-Line Regimens for the Treatment of Transplant Ineligible Patients with Multiple Myeloma: A Network Meta-Analysis of Phase 2/3 Randomized Controlled Trials
Authors: Giri Smith , Aryal Madan R , Yu Han , Grimshaw Alyssa , Pathak Ranjan , Huntington Scott F. , Dhakal Binod 
Published: November 2019

Background: Several options exist for front-line treatment of previously untreated patients with Multiple Myeloma (MM) ineligible for hematopoietic cell transplant (HCT). Many of these have not been evaluated in head to head clinical trials. Since these patients are often old and frail, treatment regimens should have dual goals: a) maximize clinical efficacy b) minimize therapy related toxicity. However, published network meta-analysis (NMA) till date have ignored the equally important safety outcome. In this systematic review, we provide an updated comparative efficacy and safety data of various front-line treatment regimens for HCT ineligible MM patients, using a Bayesian framework.
Methods: We searched Medline, Embase, Web of Science Core Collection and the Cochrane library for published phase II/phase III RCTs from inception to October 2018 comparing at least two frontline regimens for the treatment of HCT ineligible MM patients. The primary efficacy outcome was progression free survival (PFS) whereas secondary outcomes included overall response rate (ORR) and overall Survival (OS). We defined safety as rate of all-cause and common grade 3 or higher adverse events (AE) in each arm. Risk of bias was assessed using Cochrane Risk of Bias Assessment Tool. Using aggregate data, a Bayesian random-effect hierarchical model was fit with non-informative priors and adjusting for correlation between effects in multi-arm trials. Assessment of inconsistency was performed by node-splitting approach. For toxicity, a multivariate Bayesian probit-normal regression model was fitted to the observed number of adverse events for each toxicity in an arm based meta-analytic approach. The relative ranking of agents was assessed using surface under the cumulative ranking (SUCRA) probabilities. (PROSPERO # CRD42018115364)
Results: After screening 5587 publications, we selected 27 clinical trials involving 12,194 patients comparing 25 different regimens for final analysis (table 1). 26 of these studies were incorporated into one network geometry. The median age of study participants ranged from 63 to 79 years and 47% were females (table 1). Our NMA showed that for PFS, the three most effective regimens were: Daratumumab, Bortezomib, Melphalan and Prednisone (Dara-VMP, SUCRA 0.960) followed by Daratumumab, lenalidomide and dexamethasone (Dara-RD, SUCRA 0.847) and Bortezomib, melphalan, prednisone, thalidomide followed by maintenance with bortezomib-thalidomide (VMPT-VT, SUCRA 0.834), with results consistent for ORR and OS (table 2). For safety, we extracted data on 33 different grade ¾ AEs, 7 of which were reported by >50% of studies (anemia, neutropenia, thrombocytopenia, infections, neuropathy, thrombosis and gastrointestinal AEs) and used for further analyses. Among the three most efficacious regimens, the toxicity profile was most favorable for Dara-RD (median additional AEs per patient vs dexamethasone=0.74; 95% CrI 0.51-1.17; SUCRA 0.430) followed by Dara-VMP (median additional AE 0.91; 95% CrI 0.65-1.34; SUCRA 0.279) and VMPT-VT (median additional AE 0.98; 95% CrI 0.79-1.24; SUCRA 0.224) (figure 3).
Conclusion: We provide direct/indirect comparison of efficacy and safety of various frontline regimens for HCT ineligible MM patients. While Dara-VMP was most likely to be the most efficacious regimen, Dara-RD provided the best balance between efficacy and safety. The results of our analysis should provide guidance to clinicians and patients in choosing the right regimen tailored to individual patient needs.

Disclosures
Huntington: Celgene: Consultancy, Research Funding; Genentech: Consultancy; Bayer: Consultancy, Honoraria; DTRM Biopharm: Research Funding; Pharmacyclics: Honoraria; AbbVie: Consultancy. Dhakal:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees.