Immune-based therapies in the management of multiple myeloma

Abstract

Multiple myeloma (MM) is a clonal plasma cell malignancy affecting a predominantly elderly population. The continued development of newer therapies with novel mechanisms of action has reshaped the treatment paradigm of this disorder in the last two decades, leading to a significantly improved prognosis. This has in turn resulted in an increasing number of patients in need of therapy for relapsed/refractory disease. Immune-based therapies, including monoclonal antibodies, immune checkpoint inhibitors, and most promisingly, adoptive cellular therapies represent important therapeutic strategies in these patients due to their non-cross resistant mechanisms of actions with the usual frontline therapies comprising of immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). The anti-CD38 antibodies daratumumab and more recently isatuximab, with their excellent efficacy and safety profile along with its synergy in combination with IMiDs and PIs, are being increasingly incorporated in the frontline setting. Chimeric antigen receptor–T cell (CART) therapies and bi-specific T-cell engager (BiTE) represent exciting new options that have demonstrated efficacy in heavily pretreated and refractory MM. In this review, we discuss the rationale for use of immune-based therapies in MM and summarize the currently available literature for common antibodies and CAR-T therapies that are utilized in MM.

Rapid Progress in Immunotherapies for Multiple Myeloma: An Updated Comprehensive Review

“…The development of antibodies in the treatment of cancers has been accelerating, and increasing evidence has shown that antibody therapies have marked efficacy and improve the outcome of patients with cancer [ 4 , 5 , 6 , 7 , 8 , 9 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ]. Rituximab, obinutuzumab [ 57 , 58 , 59 ], brentuximab vedotin (BV) [ 60 , 61 , 62 ], blinatumomab [ 63 , 64 , 65 ], and inotuzumab ozogamicin [ 66 , 67 , 68 , 69 ] have already used in combination with chemotherapy regimens in malignant lymphoma or acute lymphoblastic leukemia.…”

“…The treatment approaches in MM have exponentially increased over the last two decades with the emergence of the proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies (mAb) in addition to autologous hematopoietic stem cell transplantation (auto-HSCT), which have substantially improved both response rates and the survival of MM patients [ 4 , 5 , 6 , 7 , 8 , 9 ], followed by the development of the second generation of novel PIs; carfilzomib [ 10 , 11 , 12 ], ixazomib [ 13 , 14 ] and IMiDs; lenalidomide and pomalidomide [ 15 , 16 , 17 ] ( Figure 1 ). The first-generation IMiD, thalidomide, exhibited cytotoxicity in older patients with MM [ 4 , 5 , 6 ]. The second-generation IMID, lenalidomide, revealed more potent cytotoxic potential than thalidomide and also reduced its toxicities.…”

“…The second-generation IMID, lenalidomide, revealed more potent cytotoxic potential than thalidomide and also reduced its toxicities. It is used as an induction therapy in combination with PIs plus dexamethasone as well as maintenance therapy with dexamethasone in patients with newly diagnosed MM (NDMM) or relapsed/refractory MM (RRMM) [ 4 , 5 , 6 , 18 ]. Furthermore, pomalidomide is about ten times more potent than lenalidomide and showed a clinical response in patients with RRMM who were refractory to lenalidomide or bortezomib.…”

“…Furthermore, pomalidomide is about ten times more potent than lenalidomide and showed a clinical response in patients with RRMM who were refractory to lenalidomide or bortezomib. The third-generation IMiD of pomalidomide plus dexamethasone had shown a better response than these agents alone [ 4 , 5 , 6 , 18 , 19 ]. However, despite considerable recent advances in the treatment modalities of MM, the disease still remains incurable, and relapse is eventually inevitable for the majority of patients because of the heterogeneity, immune evasion, and persistence of drug-resistant clonal evolution, so it remains a serious issue [ 20 , 21 , 22 ].…”

“…Recently, cellular immunotherapies, directly targeting tumor-specific cell surface antigens, exhibiting more potent immune effector cells against tumor cells by redirecting or activating various effector-mediated killing of target cells, as well as revitalizing and reversing immunotolerance towards tumor cells, has become a rapidly evolving field for the treatment of MM [ 4 , 5 , 6 , 7 , 8 , 9 , 20 , 21 , 22 ]. The monoclonal antibodies (mAbs), daratumumab and elotuzumab, targeting CD38 and SLAMF7, respectively, were the first approved immunotherapies for MM in 2015 [ 23 , 24 , 25 , 26 , 27 , 28 , 29 ].…”