Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma

Abstract

Immunotherapeutic strategies are emerging as promising therapeutic approaches in multiple myeloma (MM), with several monoclonal antibodies in advanced stages of clinical development. Of these agents, CD38-targeting antibodies have marked single agent activity in extensively pretreated MM, and preliminary results from studies with relapsed/refractory patients have shown enhanced therapeutic efficacy when daratumumab and isatuximab are combined with other agents. Furthermore, although elotuzumab (anti-SLAMF7) has no single agent activity in advanced MM, randomized trials in relapsed/refractory MM have demonstrated significantly improved progression-free survival when elotuzumab is added to lenalidomide-dexamethasone or bortezomib-dexamethasone. Importantly, there has been no significant additive toxicity when these monoclonal antibodies are combined with other anti-MM agents, other than infusion-related reactions specific to the therapeutic antibody. Prevention and management of infusion reactions is important to avoid drug discontinuation, which may in turn lead to reduced efficacy of anti-MM therapy. Therapeutic antibodies interfere with several laboratory tests. First, interference of therapeutic antibodies with immunofixation and serum protein electrophoresis assays may lead to underestimation of complete response. Strategies to mitigate interference, based on shifting the therapeutic antibody band, are in development. Furthermore, daratumumab, and probably also other CD38-targeting antibodies, interfere with blood compatibility testing and thereby complicate the safe release of blood products. Neutralization of the therapeutic CD38 antibody or CD38 denaturation on reagent red blood cells mitigates daratumumab interference with transfusion laboratory serologic tests. Finally, therapeutic antibodies may complicate flow cytometric evaluation of normal and neoplastic plasma cells, since the therapeutic antibody can affect the availability of the epitope for binding of commercially available diagnostic antibodies.

Ibrutinib alone or with dexamethasone for relapsed or relapsed and refractory multiple myeloma: phase 2 trial results

“…In PCYC‐1119, ibrutinib (840 mg) in combination with carfilzomib and dex has already shown early promising results with an initial ORR of 58%, a CBR of 67%, and no dose‐limiting toxicities during dose escalation (Chari et al , 2015). Additionally, augmenting the efficacy of immune therapies, such as monoclonal antibodies, with selective inhibitors, such as ibrutinib, is emerging as an area of great interest (Laubach & Richardson, 2015; van de Donk et al , 2016). Given the safety and activity of ibrutinib presented, future evaluation in combinations with next‐generation, small‐molecule inhibitors, monoclonal antibodies, and checkpoint inhibitors in patients with RRMM will allow evaluation of synergy across drug classes and with different targets with the hope to identify regimens that will provide greatest benefit to patients (Bianchi et al , 2015).…”

Monoclonal antibodies for treating multiple myeloma - a new era, new safety considerations?

“…This complicates the evaluation of complete responses, causing unexpected falsepositive results. Moreover, daratumumab interferes with routine pre-transfusion laboratory tests, because CD38 is also present on the surface of red blood cells, possibly leading to false-positive results of the indirect antiglobulin tests (IATs) [1]. New laboratory tests are, therefore, needed and are under evaluation to overcome these 'new adverse events'.…”

“…CD38-targeting antibodies kill MM cells via CDC, ADCC, ADCP, direct induction of apoptosis, and modulation of CD38 ectoenzyme function [1]. Currently, there are three anti-CD38 MoAbs under clinical development for MM patients: daratumumab, SAR650984, and MOR202 (Table 1).…”

“…It is involved in MM cell adhesion to bone marrow stromal cells (BMSCs); inhibition of apoptosis by regulating pro-and anti-apoptotic pathways, lowering phosphorylation of ERK1, AKT, and STAT; and regulation of NK cell cytolytic activity [1].…”

“…Alternatively, they may target bone marrow microenvironment, resulting in neutralization of growth factors, inhibition of angiogenesis, modulation of mediators of bone disease, or enhancement of the host antitumor immune response ( Figure 1) [1].…”