Therapeutics to harness the immune microenvironment in multiple myeloma

Abstract

Multiple myeloma (MM) remains an incurable, genetically heterogeneous disease characterized by the uncontrolled proliferation of transformed plasma cells nurtured within a permissive bone marrow (BM) microenvironment. Current therapies leverage the unique biology of MM cells and target the immune microenvironment that drives tumor growth and facilitates immune evasion. Proteasome inhibitors and immunomodulatory drugs were initially introduced to complement and have now supplanted cytotoxic chemotherapy as frontline anti-myeloma agents. Recently, monoclonal antibodies, bispecific antibodies, and chimeric antigen receptor T cells were developed to revamp the immune system to overcome immune suppression and improve patient responses. While current MM therapies have markedly extended patient survival, acquired drug resistance inevitably emerges and drives disease progression. The logical progression for the next generation of MM therapies would be to design and validate agents that prevent and/or overcome acquired resistance to immunotherapies. The complex BM microenvironment promotes resistance to both current anti-myeloma agents and emerging immunotherapies. Myeloma cells are intertwined with a complex BM immune microenvironment that contributes to the development of adaptive drug resistance. Here, we describe recently FDA-approved and investigational anti-myeloma agents that directly or indirectly target the BM microenvironment to prevent or overcome drug resistance. Synergistic effects of anti-myeloma agents may foster the development of rationally-designed drug cocktails that prevent BM-mediated resistance to immunotherapies.

Targeting TGF-β signaling in the multiple myeloma microenvironment: Steering CARs and T cells in the right direction

“…TGF-β acts as a chemoattractant that draws monocytes to inflammatory sites and upregulates adhesion molecules that facilitate monocyte attachment to the ECM. The TGF-β-rich TME further contributes to immune suppression by squelching macrophage activity ( Ignatz-Hoover and Driscoll, 2022 ).…”

Road testing new CAR design strategies in multiple myeloma

“…Since the turn of the century, the myeloma field has witnessed two paradigm-shifting approaches that rapidly yielded clinical benefit and abruptly altered treatment patterns ( 7 ). Since plasma cells (PCs) are professional antibody-producing factories, myeloma cells are exquisitely sensitive to proteasome inhibitors (PIs) that disrupt protein homeostasis ( 8 – 12 ). Clinical success of the first U.S. Food and Drug Administration (FDA)-approved PI bortezomib launched a meteoric rise in interest of MM by basic scientists, physicians and the pharmaceutical industry ( 5 – 7 , 13 – 15 ).…”

A Fully Human IgE Specific for CD38 as a Potential Therapy for Multiple Myeloma

“…Multiple myeloma (MM) is a malignancy of plasma cells characterized by osteolytic bone lesions, hypercalcemia, renal failure, anemia, and neuropathy [ 1 , 2 ]. It is the second most common hematologic malignancy in the United States and remains incurable despite the advances in treatment strategies including immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies of the IgG class [ 1 , 2 , 3 , 4 ].…”

“…Multiple myeloma (MM) is a malignancy of plasma cells characterized by osteolytic bone lesions, hypercalcemia, renal failure, anemia, and neuropathy [ 1 , 2 ]. It is the second most common hematologic malignancy in the United States and remains incurable despite the advances in treatment strategies including immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies of the IgG class [ 1 , 2 , 3 , 4 ]. One such monoclonal antibody is daratumumab (Darzalex ® ), which is a first-in-class anti-CD38 monoclonal antibody for MM treatment approved by the Food and Drug Administration (FDA) as a monotherapy for relapsed and refractory MM in 2015 and in combination with either bortezomib and dexamethasone or lenalidomide and dexamethasone in 2016 [ 2 , 5 ].…”

“…It is the second most common hematologic malignancy in the United States and remains incurable despite the advances in treatment strategies including immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies of the IgG class [ 1 , 2 , 3 , 4 ]. One such monoclonal antibody is daratumumab (Darzalex ® ), which is a first-in-class anti-CD38 monoclonal antibody for MM treatment approved by the Food and Drug Administration (FDA) as a monotherapy for relapsed and refractory MM in 2015 and in combination with either bortezomib and dexamethasone or lenalidomide and dexamethasone in 2016 [ 2 , 5 ]. Daratumumab, a fully human IgG1 antibody, eliminates MM cells expressing CD38 through various direct mechanisms: antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell mediated-phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), and induction of programmed cell death (apoptosis) in the presence of a cross-linking antibody [ 6 , 7 , 8 ] as well as immunomodulatory mechanisms [ 9 , 10 ].…”