Daratumumab added to standard of care in patients with newly diagnosed multiple myeloma: A network meta‐analysis

Abstract

Purpose: To investigate the activity and safety of daratumumab added to standard of care and evaluate the relative efficacy of DRd vs DVMP and other regimens on survival endpoints for untreated myeloma, we undertook this meta-analysis. Methods:We searched published reports that described the activity and safety of daratumumab added to standard of care for untreated myeloma. Results: Six daratumumab trials were identified, covering 5106 subjects. Daratumumab containing combinations for untreated myeloma attained an impressive complete response or better (≥CR) rate of 24%, very good partial response or better (≥VGPR) rate of 67%, overall response rate (ORR) of 92%. Daratumumab added to standard of care significantly improved progression free survival (PFS): the HR for PFS was 0.52 [0.44, 0.61], P < .001. The HR for overall survival (OS) was 0.73 [0.52, 1.04], P = .09. In the network meta-analysis for patients ineligible for autologous stem-cell transplantation (ASCT), DRd regimen produced significant PFS advantage vs other first-line treatments (VMP HR:0.39 P < .001, Rd HR:0.55 P < .001, MPT HR:0.38 P < .001, and MP HR:0.22 P < .001); DVMP regimen also produced significant PFS advantage vs VMP (HR:0.50 P < .001), MPT (HR:0.49 P < .001), and MP (HR:0.28 P < .001). Among these first-line regimens (DRd, DVMP, VMP, Rd, MPT, and MP), DRd regimen had the highest probability to be the best intervention, with 83.4% and 91.0% probability to reach the longest PFS and OS, respectively. Toxicity consisted primarily of myelosuppression. And, the vital non-hematologic adverse events (AEs) were peripheral sensory neuropathy (41% of all grades) and upper respiratory tract infection (39% of all grades).Conclusions: Daratumumab added to standard of care could produce clinical benefits in newly diagnosed patients with multiple myeloma. DRd and DVMP could be good combination options for those patients ineligible for ASCT. K E Y W O R D Sdaratumumab, front-line, meta-analysis, multiple myeloma

Treatment Regimens for Transplant-Ineligible Patients With Newly Diagnosed Multiple Myeloma: A Systematic Literature Review and Network Meta-analysis

“…A We found that both daratumumab-containing regimens evaluated (D-Rd and D-VMP) and VRd consistently had better PFS than Rd continuous; this finding was also seen in the simplified network of comparators relevant for Europe despite the different SOC options. These results are consistent with those of previous NMAs, including Cao et al [9], Ramasamy et al [13], and Xu et al [12] (D-Rd versus Rd PFS HRs, 0.57, 0.57, and 0.55, respectively). Cao et al also observed an advantage for D-VMP versus Rd (PFS HR, 0.59) [9], whereas the other studies were favourable but with different point estimators (PFS HRs, 0.73 and 0.71, respectively) [12,13].…”

“…These results are consistent with those of previous NMAs, including Cao et al [9], Ramasamy et al [13], and Xu et al [12] (D-Rd versus Rd PFS HRs, 0.57, 0.57, and 0.55, respectively). Cao et al also observed an advantage for D-VMP versus Rd (PFS HR, 0.59) [9], whereas the other studies were favourable but with different point estimators (PFS HRs, 0.73 and 0.71, respectively) [12,13]. This divergence in benefit is potentially attributable to the different data cut-offs for ALCYONE and VISTA used in the analyses.…”

“…Previous NMAs performed in this setting since 2019 have identified VRd, daratumumab in combination with VMP (D-VMP), and daratumumab in combination with Rd (D-Rd) as the most effective regimens in terms of progressionfree survival (PFS) and/or overall survival (OS) [8][9][10][11][12][13][14][15]. The results from these analyses also emphasize the benefits obtained from the use of triplet or quadruplet regimens.…”

Roles of CD38 in the Immune Response to Infection

“…The mechanism of action of daratumumab is based on the elimination of tumor cells expressing high levels of CD38 through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Recent studies have reported an increased risk of infection in multiple myeloma patients undergoing treatment with daratumumab, either as monotherapy or as combined therapy with other drugs, with some cases resulting in lethal sepsis [87][88][89][90][91][92][93]. Infections reported as drug-related adverse effects include opportunistic bacterial infections of the respiratory or urinary tracts (e.g., S. pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli and Haemophilus influenzae), exogenous viral infections (e.g., acute respiratory syncytial virus, human metapneumovirus and influenza A and B viruses) and viral reactivations (e.g., cytomegalovirus, herpes simplex virus and varicella-zoster virus).…”

Addition of daratumumab to multiple myeloma backbone regimens significantly improves clinical outcomes: a systematic review and meta-analysis of randomised controlled trials

“…Xu et al found that addition of daratumumab to first-line regimens (bortezomib, melphalan, and prednisone or lenalidomide and dexamethasone) significantly improves PFS, compared to the same regimens alone, in NDMM. Furthermore, in their study, patients receiving daratumumab, compared to patients on the control arms, had a higher chance to achieve complete response (CR) rate or better 7 . Similar benefit of daratumumab was found by Wang et al regarding CR or better in relapsed/refractory MM (RRMM) 8 .…”