Monoclonal Antibodies to Treat Multiple Myeloma: A Dream Come True

Abstract

Immunotherapy is increasingly used in the treatment of multiple myeloma (MM). Monoclonal antibodies (mAbs) are safe and effective ways to elicit immunotherapeutic responses. In 2015, daratumumab has become the first mAb approved by the Food and Drug Administration for clinical use in MM and, in the last 5 years, a lot of clinical and preclinical research has been done to optimize the use of this drug class. Currently, mAbs have already become part of standard-of-care combinations for the treatment of relapsed/refractory MM and very soon they will also be used in the frontline setting. The success of simple mAbs (‘naked mAbs’) prompted the development of new types of molecules. Antibody–drug conjugates (ADCs) are tumor-targeting mAbs that release a cytotoxic payload into the tumor cells upon antigen binding in order to destroy them. Bispecific antibodies (BiAbs) are mAbs simultaneously targeting a tumor-associated antigen and an immune cell-associated antigen in order to redirect the immune cell cytotoxicity against the tumor cell. These different constructs produced solid preclinical data and promising clinical data in phase I/II trials. The aim of this review article is to summarize all the recent developments in the field, including data on naked mAbs, ADCs and BiAbs.

Synergistic Effects of Venetoclax and Daratumumab on Antibody-Dependent Cell-Mediated Natural Killer Cytotoxicity in Multiple Myeloma

“…Our data correlated with those from a previous case report [ 13 ] and with the currently reported results of phase I/II trials for patients with MM [ 14 , 15 ]. A case report of a patient with relapsed plasma cell leukemia and t(11;14) treated with a combination therapy of venetoclax, daratumumab, and dexamethasone showed a rapid decrease in tumor burden [ 13 ].…”

“…Our data correlated with those from a previous case report [ 13 ] and with the currently reported results of phase I/II trials for patients with MM [ 14 , 15 ]. A case report of a patient with relapsed plasma cell leukemia and t(11;14) treated with a combination therapy of venetoclax, daratumumab, and dexamethasone showed a rapid decrease in tumor burden [ 13 ]. Another group reported a phase I/II trial comprising 48 patients with R/R MM that were treated with a combination therapy of venetoclax and daratumumab to evaluate the efficacy and safety of this treatment strategy.…”

The Role of Monoclonal Antibodies in the First-Line Treatment of Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma

“…Future trials should be designed on specific populations according to frailty status: Now that we have access to new immunotherapeutic agents (ADCs, BiAbs) [ 12 ], in which population should we explore using them? BiAbs should be explored for the treatment of fit patients, where efficacy and the achievement of deep responses are the treatment goals, and patients are likely to have enough organ function to tolerate neurotoxicity/cytokine release syndrome and/or infections.…”

“…The advent of immunotherapy revolutionized the treatment scenario for MM patients [ 11 , 12 , 13 , 14 ]. The anti-CD38 monoclonal antibody (mAb) daratumumab has been included in the standard-of-care regimens for NTE newly diagnosed (ND)MM patients following the results of the phase III ALCYONE trial, which compared daratumumab plus bortezomib, melphalan and prednisone (Dara-VMP) to VMP, and the MAIA trial, which compared daratumumab plus lenalidomide and dexamethasone (Dara-Rd) to Rd [ 15 , 16 ].…”

Genome Instability in Multiple Myeloma: Facts and Factors

“…CD38 functions as a cell receptor, adhesion molecule, and ectoenzyme involved in the modulation of many essential cell processes, including immune cell response and signaling [ 271 ]. Daratumumab, the anti-CD38 antibody, is approved for MM treatment as a single agent or in combination with other therapies [ 87 , 270 , 272 ]. Daratumumab induces complement-dependent cytotoxicity and antibody-dependent, cell-mediated cytotoxicity and phagocytosis [ 269 ].…”