Antibodies and bispecifics for multiple myeloma: effective effector therapy

Abstract

The therapeutic landscape in multiple myeloma (MM) has changed dramatically over the last 2 decades. With the introduction of novel immunotherapies, patients with MM can expect deeper responses, longer remissions, and improved overall survival. Since its approval by the US Food and Drug Administration in 2015, the monoclonal antibody specific for CD38, daratumumab, has been incorporated into both frontline and relapsed treatment regimens. Its role as a maintenance therapy is currently being explored. Subsequently, a variety of novel antibody therapeutics have evolved from the success of daratumumab, using similar concepts to target the malignant plasma cell clone. Noteworthy naked monoclonal antibodies include isatuximab, another agent directed against CD38, and elotuzumab, an agent directed against SLAM family member 7. Antibody-drug conjugates, complex molecules composed of an antibody tethered to a cytotoxic drug, target malignant cells and deliver a lethal payload. The first to market is belantamab mafodotin, which targets B-cell maturation antigen (BCMA) on malignant plasma cells and delivers a potent microtubule inhibitor, monomethyl auristatin F. Additionally, bispecific T-cell antibodies are in development that engage the immune system directly by simultaneously binding CD3 on T cells and a target epitope—such as BCMA, G-protein coupled receptor family C group 5 member D (GPRC5d), and Fc receptor homologue 5 (FcRH5)—on malignant cells. Currently, teclistamab, an anti-BCMA bispecific, is closest to approval for commercial use. In this review, we explore the evolving landscape of antibodies in the treatment of MM, including their role in frontline and relapse settings.

Treatment with low‐dose, single‐agent belantamab mafodotin is safe and provides long‐term responses in heavily pretreated multiple myeloma patients

“…Moreover, the incidence and severity of infections were both lower than reported in most previous studies, reflecting the suppression of normal plasma cells was weaker than induced by the standard B-MAF dose or by bispecific T-cell engagers (BiTEs), which have a higher anti-MM activity, but also a greater risk for infections. 13 According to our analysis, most patients responded and improved their responses over the first few months of therapy, reaching VGPR/ CR. These results, which are superior to those reported in most prospective and retrospective real-world studies, 1,4,5,7,8,14,15 might reflect the decreased ocular toxicity achieved with our low-dose belantamab strategy, enabling continues treatment and deepening of response.…”

Management of patients with multiple myeloma and COVID-19 in the post pandemic era: a consensus paper from the European Myeloma Network (EMN)

“…They may develop acute respiratory distress syndrome (ARDS) and thrombotic complications that can induce high in-hospital mortality [ 25 ]. This is due to MM patients’ advanced age, co-existing medical conditions, as well as to humoral and cellular immunity compromised by the disease itself and by concomitant, often prolonged-applied targeted and immunosuppressive therapies, including steroids, monoclonal antibodies [ 26 , 27 ], ASCT [ 28 ], and novel cellular therapies [ 29 , 30 ]. Furthermore, MM patients often show low/suboptimal rates (in terms of percentage of responders and magnitude of response) of both humoral and functional T-cell immune responses to anti-SARS-CoV-2 vaccines [ 31 – 34 ]; this further contributes to an increased risk of severe COVID-19, need of hospitalization and higher mortality rates [ 35 ].…”

Selinexor: Targeting a novel pathway in multiple myeloma

“…As a consequence, the 5‐year relative survival rate has increased from 34.5% in the year 2000 to almost 60% at the present time [3], and a growing proportion of patients with newly diagnosed MM (NDMM) can expect to survive for more than 10 years, thanks to increasingly durable frontline responses [4], and/or achieve functional cure through deep, sustained, minimal‐residual‐disease‐negative remissions [5]. In 2023, three key classes of agents form the backbone of the MM treatment algorithm: the proteasome inhibitors (PIs) – bortezomib, carfilzomib and ixazomib [6]; thalidomide and the immunomodulatory drugs lenalidomide and pomalidomide [7]; and, within the past 10 years, monoclonal antibodies (mAbs) – daratumumab and isatuximab, targeting CD38, and elotuzumab, targeting SLAMF7 [8]. Triplet therapies and quadruplet therapies based on these three drug classes, combined with dexamethasone, are among the existing and emerging standard‐of‐care options in both NDMM and relapsed/refractory MM (RRMM) [2, 9, 10].…”

“…Triplet therapies and quadruplet therapies based on these three drug classes, combined with dexamethasone, are among the existing and emerging standard-of-care options in both NDMM and relapsed/refractory MM (RRMM) [2,9,10]. Additionally, novel therapies targeting B-cell maturation antigen (BCMA) have emerged recently as a fourth key drug class for the treatment of MM, following the approvals of two BCMA-directed chimeric antigen receptor (CAR) T-cell therapies, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) [11], the bispecific antibody teclistamab, which targets BCMA on MM cells and CD3 on T cells [8,12] and the anti-BCMA antibody-drug conjugate belantamab mafodotin [13] (which, following accelerated approval, has had US marketing authorisation withdrawn following the phase 3 DREAMM-3 trial not meeting its primary endpoint, but which remains under investigation in combination regimens in multiple studies including DREAMM-5, DREAMM-7 and DREAMM-8 based on promising efficacy in preliminary studies).…”

“…With MM being a cancer sensitive to immune surveillance, multiple immunebased therapies-in addition to ide-cel, cilta-cel and teclistamab-are being developed that show substantial activity in RRMM [19]. These include novel antibody-drug conjugates [13] and bispecific antibodies/T cell engagers such as talquetamab [8,12] that target other antigens specific to MM cells, such as CD38, G protein-coupled receptor, class C, group 5, member D (GPRC5D) and Fc receptor-homolog 5 (FcRH5), and co-opt or stimulate the patient's immune system to fight against the disease. Furthermore, following on from the immunomodulatory drugs, a next-generation class of agents-cereblon E3 ligase modulators [20]-is also showing promising early results in the RRMM setting.…”