FRONTLINE THERAPY FOR NON-TRANSPLANT ELIGIBLE MULTIPLE MYELOMA: A CRITICAL APPRAISAL OF PUBLISHED NETWORK META-ANALYSES

Newly diagnosed multiple myeloma (MM) who are transplant ineligible (NTE NDMM) are usually treated with multiple-drug combinations including proteasome inhibitors, immunomodulatory drugs and alkylating agents. Recently approved combo therapies including anti-CD38 monoclonal agents and/or lenalidomide improve progression-free survival (PFS) as compared with one of the standard treatments. We thus aimed at assessing the relative efficacy of novel daratumumab-based and lenalidomide based triplets/quadruplets as compared with overall standard treatments for NTE NDMM, namely Rd and VMP. Network meta-analyses (NMA) are accepted evidence-based tools for conducting indirect comparisons among treatments, however, the scientific community is still skeptical regarding their robustness. We, therefore conducted an umbrella review: fully published NMAs were retrieved by standard searches (EBMASE, Cochrane Library, MEDLINE/PubMed) and appraised by AMSTAR-2 and ROBIS tools. Three indirect comparisons of PFS were targeted: 1) VRD versus VMP, 2) DaraRd versus VMP, 3) DaraVMP versus Rd. Overall 17 NMA addressing NDMM were published since Jan 2017: 6 fully published ones including both daratumumab- and lenalidomide-based novel treatments were appraised. The overall quality of the NMAs was poor to moderate according to AMSTAR-2 and ROBIS. Each NMA analyzed 6 to 27 trials and 2 ones were company sponsored. 1) VRD was compared to VMP by 3 moderate-quality NMAs, which consistently reported a significant amelioration of PFS or higher SUCRA of VRD, while OS-HR was not conclusive. 2) DaraRd was compared to VMP by 4 NMAs and the pooled PFSHR ranged from 0.39 to 0.61. A significant amelioration of OS was also reported by the unique NMA assessing this endpoint. 3) DaraVMP was compared versus Rd by 4 NMAs. Pooled HR ranged from 0.35 to 0.71, which was statistically significant in two ones. DaraVMP achieved the highest SUCRA (0.960) in the latest and largest NMA (Giri et al 2020). Only one NMA compared OS of the two regimens and did not report a significant advantage of DaraVMP. In conclusion, Dara-VMP, VRD and Dara-Rd show mostly a favorable PFS profile as both directly and indirectly compared with standard frontline treatments for NTE NDMM. NMAs are valuable evidence-based tools, however, their quality needs to be appraised before using their result to support clinical recommendations. Future NMAs are expected to incorporate also safety endpoints in order to allow benefit to risk assessments.