Advancements in Treatment for Newly Diagnosed Frail and Elderly Myeloma Patients: A Systematic Review

Introduction: About 60% newly diagnosed multiple myeloma (NDMM) cases are above age of 60 years. The paucity of studies exclusively targeting management of frail patients has led to persistence of therapeutic uncertainties. With data on more than ten thousand patients, purpose of this review is to summarize the available therapeutic options with emphasis on recent advances for treatment of frail and elderly, transplant ineligible NDMM patients. Methods: We performed a comprehensive literature search on June 1st, 2019 on PubMed, Cochrane Library and ClinicalTrials.gov. We used the MeSH terms: ‘Multiple Myeloma’ and ‘Frail Elderly’, with associated entry words. Search yielded 71 studies regarding our topic of interest. Following PRISMA guidelines and subsequent screening by two reviewers, we shortlisted 19 ongoing/completed studies (n=10297) and included data from these studies in our systematic review. Results:1.Two/Three Drug regimens: Among the two drug regimens [Table 1], Lenalidomide (R) and Dexamethasone (D) (RD) combination has been most widely studied (n=1445). RD yielded objective response rate (ORR) of 81.3%, complete response (CR) or above of 24.9% and progression free survival (PFS) of 31.9 months in a phase III trial (Usmani, 2019) (n=369). Facon et al. (2019) [n=368] used Daratumumab (Dara)+R+D (DaraRD) which exhibited the best response overall with an ORR of 92.9%, CR of 47.6%, VGPR of 31.8% while the PFS was not reached till study end point. However, >grade 3 neutropenia developed in 50% patients. Three-drug regimen of Bortezomib(V)+Melphalan(M)+Prednisolone(P) (VMP) has been the most widely studied regimen (n=1059) in four phase II/III clinical trials. In a phase II trial (Kizaki, 2016) (n=87), VMP yielded a PFS of 36 months and CR of 25%. In a Phase II trial by Larocca et al (2016, n=148), 3 cohorts (VP, V+ Cyclophosphamide (C) +P and VMP respectively) were studied. Best response was achieved by VMP with ORR of 86%, PFS of 17.1 months and CR of 14%, compared with VCP (ORR=67%, PFS=15.2 months and CR=2%) and VP (ORR=64%, PFS=14 months, CR=8%). However, the discontinuation rate (DR) due to AEs for VMP was relatively high (20%). A phase III trial (San-Miguel, 2018) (n=955) compared Carfilzomib(K)+M+P (KMP) against VMP. Median PFS was found to be 22.3 months with KMP Vs 22.1 months with VMP. Grade ≥3 AE rates were 74.7% for KMP and 76.2% for VMP. Thus, the results showed no significant difference between both regimens. Thalidomide (T) has also