Systematic review and meta-analysis of the efficacy and safety of novel monoclonal antibodies for treatment of relapsed/refractory multiple myeloma

Abstract

Although two newly launched monoclonal antibodies (mAbs), elotuzumab and daratumumab, performed well in patients with relapsed or relapsed/refractory multiple myeloma (RRMM), their efficacy and safety remain uncertain. We therefore performed a systematic review and meta-analysis of the most recent clinical trials that evaluated elotuzumab and/or daratumumab for the treatment of patients with RRMM. Our meta-analysis included 13 clinical trials with 2,402 patients participating. The overall response rate (ORR) was 57% (95% confidence interval [CI]: 38-76%), and the at least very good partial response rate (VGPR) was 32% (95% CI: 19-46%). mAb-based regimens prolonged progression-free survival (PFS, hazard ratio: 0.52, 95% CI: 0.36-0.75) compared to non-mAb-based regimens. Additionally, the efficacy of triplet regimens was superior to that of single or doublet regimens. The same trend was observed in a subgroup analysis of daratumumab and elotuzumab. The most common grade 3/4 adverse events included neutropenia, lymphopenia, thrombocytopenia, anemia, leukopenia, pneumonia, and fatigue. Elotuzumab and daratumumab improved the ORR, at least VGPR, and PFS compared to non-mAb-based regimens. In a pooled analysis, both mAbs had promising efficacy and safety profiles, particularly in triplet regimens. The same trend was observed in daratumumab- and elotuzumab-based regimens. Daratumumab triplet therapy (daratumumab, lenalidomide, and dexamethasone) was superior to other triplet regimens for the treatment of RRMM, and daratumumab monotherapy was more effective than either single agent in heavily pretreated MM patients, suggesting CD38 is an effective target for treatment of RRMM. Additional clinical studies of elotuzumab and daratumumab will be required to validate these results.

Resistance to proteasome inhibitors and other targeted therapies in myeloma

“…Pembrolizumab targets the programmed death 1 (PD‐1, also termed PDCD1, CD279)/programmed cell death ligand 1 (PD‐L1, also termed CD274, PDCD1LG1) pathway, a critical initiator of immune activation, playing a role in mediating tolerance (Zhang et al , ). However, two phase III trials KEYNOTE‐183 and KEYNOTE‐185 have recently been suspended by the US FDA due to more deaths being observed in the pembrolizumab arms and further information on the use of pembrolizumab in MM is pending.…”

Monoclonal antibodies in relapsed/refractory myeloma: updated evidence from clinical trials, real-life studies, and meta-analyses

“…Botta et al, in a study of 18 trials, found that DRd ranked first among other salvage regimens per the average value between surface under the cumulative ranking curve of ORR, CR rates, PFS, OS, and safety [50]. Similar conclusions were reached by Dimopoulos et al from analysis of 82 trials comparing IMID-containing regimens [51], and Zhang et al (13 trials that evaluated treatments including, in particular, elotuzumab or daratumumab) [23]. Beurden-Tan et al, in their evaluation of 17 trials, also confirmed DRd as the best available treatment for RRMM [52].…”

“…A recently published systematic review with meta-analysis of 13 clinical trials with 2.402 patients receiving elotuzumab and/or daratumumab for the treatment of patients with RRMM found that daratumumab monotherapy was more effective than either single agent (including bortezomib and lenalidomide) in heavily pretreated RRMM [23].…”

“…Botta et al found that regimens based on elotuzumab and dexamethasone + an immunomodulator ranked fifth among 18 randomized-controlled trials in terms of PFS, ORR, and OS [50]. Meta-analysis of two studies that compared triplet elotuzumab-containing regimens with non-elotuzumab-based combinations concluded that the first regimens were more effective in terms of PFS and ORR [23]. In their network metanalysis of results from the ELOQUENT-2 (Elo-Rd) and POLLUX (DRd) trials, Dimopoulos et al calculated an HR of 0.54 for PFS and 0.82 for OS, indicating that the POLLUX regimen is statistically the most efficacious of the two [51].…”

Hematopoietic Stem Cell Transplantation in Multiple Myeloma in the Era of Novel Therapies

“…Elotuzumab is an immunostimulatory monoclonal antibody targeting signaling lymphocyte activation molecule F7 (SLAMF7) [157]. While no responses to elotuzumab as a single agent were obtained, the addition of elotuzumab to lenalidomide and dexamethasone in RR-MM patients resulted in overall response rate (ORR) of 79% compared to 66% ORR obtained with lenalidomide and dexamethasone alone [142,158]. Also, in a phase III randomized clinical trial in patients with R/R-MM, the combination of elotuzumab, lenalidomide and dexamethasone decreased the risks of death and disease progression by 30% [157].…”