Belantamab Mafodotin + Bortezomib + Dexamethasone Versus 2L+ Relapsed/Refractory Multiple Myeloma Regimens: Lenalidomide-Exposed, Lenalidomide-Refractory, High-Risk Cytogenic, and 2L-Only Subpopulations: A Network Meta-Analysis
Authors: Rodríguez-Otero Paula , Richter Joshua , Nooka Ajay K. , Schjesvold Fredrik , Combe Emily , Cooper Leanne , Schofield Ollie , Sly Indeg , Ballew Nick , Bitetti Jacopo , Boytsov Natalie , McNamara Simon , Purser Molly 
Published: December 2024

Introduction: Patients with relapsed/refractory multiple myeloma(RRMM) who are refractory to lenalidomide (len) have limited effective treatments and consequently poor outcomes. The phase III DREAMM-7 study (NCT04246047) evaluated belantamab mafodotin (B), an antibody-drug conjugate targeting B-cell maturation antigen, with bortezomib (V)+dexamethasone (d; BVd) vs daratumumab (D)+Vd (DVd) in patients with RRMM who had ≥1 prior line of therapy (2L+) and included patients who were len-exposed/refractory (Hungria et al. NEJM 2024). In the ITT analysis, BVd improved progression-free survival (PFS) vs DVd (36.6 vs 13.4 months; hazard ratio [HR] 0.41, 95% confidence interval 0.31-0.53, P&lt;0.00001). The PFS benefit was maintained in all predefined subgroups, including prior len-exposed, len-refractory, 2L-only, and high-risk cytogenetic patients.

In the absence of head-to-head trials, indirect comparisons can evaluate the relative efficacy of BVd compared with other regimens for RRMM in 2L+, including subpopulations of clinical interest, to better inform treatment decisions. A prior network meta-analysis (NMA) suggested BVd improved PFS in 2L+ RRMM compared with other proteasome inhibitor (PI)-based regimens (Richter 2024, IMS). Here, a similar analysis was performed in len-exposed, len-refractory, 2L-only, and high-risk cytogenetic subpopulations.

Methods: A systematic literature review identified randomized controlled trials (RCTs) (Jan 2008-Feb 2024) of adults with RRMM in 2L+ who had disease progression on/after most recent therapy. Only RCTs that evaluated PFS in a regimen approved/likely to be approved by the US Food and Drug Administration/European Medicines Agency, or which were of interest for health technology assessment, were included. Trials/regimens that were not part of the connected evidence networks were excluded from the NMA. Trials were linked together by the treatment(s) they shared to form connected networks of evidence, and a Bayesian NMA was conducted to assess PFS. NMAs were constructed based on the availability of regimen data within the networks for each subpopulation of interest (2L+ len-exposed, len-refractory, 2L-only and high-risk cytogenetic).

Results: All regimens compared with BVd were PI-based regimens.

The len-exposed subpopulation network comprised 8 RCTs and included the following regimens: BVd, DVd, carfilzomib (K)+ d (Kd; plus an alternative dosage), DKd, isatuximab (Isa)+ Kd (IsaKd), pomalidomide (P)+ Vd (PVd), selinexor (S)+Vd (SVd), and Vd. BVd improved PFS across all comparators, and HRs (range 0.12‒0.34) were statistically significant in favor of BVd. HRs (95% credible interval [CrI]) for BVd compared with anti-CD38 regimens included 0.34 (0.17-0.71) vs DKd, 0.29 (0.13-0.64) vs IsaKd, and 0.29 (0.19-0.43) vs DVd.

The len-refractory subpopulation network comprised 8 RCTs with the same regimens as the len-exposed population except SVd and the addition of cyclophosphamide (Cy)+ Kd (CyKd). BVd improved PFS across all comparators, and HRs were statistically significant favoring BVd, ranging from 0.14‒0.38. HRs (95% CrI) for BVd compared with anti-CD38 regimens included 0.37 (0.15-0.89) vs DKd, 0.29 (0.12-0.70) vs IsaKd, and 0.31 (0.20-0.49) vs DVd.

The 2L-only subpopulation network comprised 10 RCTs, with the same treatments as the len-exposed subgroup plus panobinostat + Vd and elotuzumab (E) + Vd. BVd improved PFS across all comparators and HRs (range 0.13‒0.52) were statistically significant favoring BVd. HRs (95% CrI) for BVd compared with anti-CD38 regimens included 0.45 (0.21-0.94) vs DKd, 0.42 (0.20-0.88) vs IsaKd, and 0.52 (0.36-0.76) vs DVd.

The high-risk cytogenic subpopulation network comprised 10 RCTs, with the same treatments as the len-exposed subgroup plus CyKd. BVd improved PFS across all comparators, and HRs (range 0.13‒0.40) were statistically significant favoring BVd except vs DKd. HRs (95% CrI) for BVd compared with anti-CD38 regimens included 0.40 (0.15-1.09) vs DKd, 0.27 (0.10-0.71) vs IsaKd, and 0.31 (0.18-0.53) vs DVd.

Conclusions: The DREAMM-7 RCT demonstrated a significant PFS benefit with BVd vs DVd in patients with ≥1L RRMM. In the absence of RCT comparing BVd to regimens (besides DVd), this NMA indicates that BVd offers improved PFS compared with other PI-based regimens for subpopulations of patients with RRMM who are len-exposed/refractory, in 2L-only, or with high-risk cytogenetic profiles.