Monoclonal antibody therapy in multiple myeloma

Abstract

The therapeutic landscape of multiple myeloma (MM) has evolved spectacularly over the past decade with the discovery and validation of proteasome inhibitors and immunomodulatory agents as highly active agents, both in front-line therapy as well as in the relapse and maintenance settings. Although previous attempts to apply available monoclonal antibodies (Mabs) to the treatment of patients with MM has until recently been disappointing, novel targets specifically explored in the context of MM have recently lead to the first approvals of Mabs for the treatment of patients with MM. We have performed a literature search to identify preclinical targeting of MM, including in vitro and in vivo models using monoclonal antibodies, as well as clinical trials of monoclonal antibodies in patients with MM. Sources used were peer-reviewed publications, congress abstracts and on-line clinical trials data (such as clinicaltrials.gov). Several targets have been evaluated in preclinical models and a growing number of agents are being evaluated in clinical trials, as single agents or in combination and under various antibody formats. Two agents, targeting for the first time CD38 and SLAMF7, respectively, have recently been approved for the treatment of patients with MM. The recent approval of these two antibodies is expected to have a strong impact on treatment modalities and outcome in patients with MM, including both transplant eligible and elderly patients.

Current developments in immunotherapy in the treatment of multiple myeloma

“…In preclinical research, elotuzumab induced cell death in MM cells via antibody-dependent cell-mediated cytotoxicity, by inhibition of MM-stromal interactions, 35 and probably by increased activity of NK cells. 40,41 Although a phase 1 trial of patients with RRMM and elotuzumab monotherapy showed no objective response, 42 another phase 1 study demonstrated an overall response rate (ORR) of 82% in patients treated with elotuzumab, lenalidomide, and dexamethasone (Elo-Rd). In a phase 2 study of lenalidomidenaive patients who were being treated with 10 or 20 mg/ kg elotuzumab, the ORR was 84%.…”

“…47,[51][52][53][54] Interestingly, other CD38 mAbs under development, isatuximab and MOR202, show similar but not identical effects on MM cells because they do not act via all the mechanisms of daratumumab. 41,55 In a phase 1/2 study, daratumumab proved to have dose-dependent antimyeloma activity in RRMM, with ORRs of 10% and 36% with 8 and 16 mg/kg, respectively (NCT00574288). 16 In a phase 2 study with 106 patients, after at least 3 lines of therapy, the higher daratumumab dose led to an ORR of 29% (with 3 stringent complete responses [sCRs], 10 very good partial responses [VGPRs], and 18 partial responses [PRs]) and a median PFS of 3.7 months (NCT01985126).…”

Chimeric antigen receptor T-cell therapies for multiple myeloma

“…72,73 Two monoclonal antibodies against CD38 have been tested clinically, daratumumab and isatuximab. 75,76 Used as a single agent, daratumumab had a 36% response rate in patients with refractory myeloma. 77 Drent et al have demonstrated in preclinical work that anti-CD38 CAR-Ts proliferate, produce cytokines, and lyse CD38 1 MM cells; however, these CAR-Ts lysed not only CD38…”

A blockage monoclonal antibody protocol as an alternative strategy to avoid anti‐CD38 interference in immunohematological testing

“…Despite the improvement, the disease typically relapses and new classes of drugs are needed . Monoclonal antibodies represent a novel class of therapeutics in MM, targeting different antigens on plasma cells . Of these targets, anti‐CD38 antibodies are in advanced stages of clinical development, with the approval of daratumumab (DARA) for the treatment of MM patients in November 2015 by the US Food and Drug Administration …”

“…2 Monoclonal antibodies represent a novel class of therapeutics in MM, targeting different antigens on plasma cells. 3,4 Of these targets, anti-CD38 antibodies are in advanced stages of clinical development, with the approval of daratumumab (DARA) for the treatment of MM patients in November 2015 by the US Food and Drug Administration. [5][6][7] The use of DARA and other anti-CD38 therapies leads to interference with routine immunohematological tests, ABBREVIATIONS: AHG = antihuman globulin; BMAP = blockage monoclonal antibody protocol; DARA = daratumumab; DAT = direct antiglobulin test; DTT = dithiothreitol; IATs = indirect antiglobulin tests; MM = multiple myeloma.From the…”